Prodrugs of 4’-c-substituted-2-halo-2’-deoxyadenosine nucleosides and methods of making and using the same

Abstract

This invention provides a 4'-C-substituted-2-halo-2'-deoxyadenosine prodrug, as well as compositions, methods, and kits thereof. These compounds can be used to treat viral infections, including but not limited to human immunodeficiency virus (HIV).

Description

Technical Field

[0001] This invention relates to compounds, compositions, and methods for treating viral infections. Prior Technology

[0002] Human immunodeficiency virus (HIV) infection is a serious, life-threatening disease affecting millions worldwide and of great public health significance. There is currently no cure, and those affected by HIV may require lifelong treatment, which may include taking one or more medications daily and can have various side effects. Improvements in the treatment of HIV and other viral infections are hoped for. Summary of the Invention

[0003] This article reveals (for example) equation ( [I]) Compound: (I) in The dashed line (----) together with the parallel solid line represents a double bond, depending on the situation; X represents halogen; R1 represents a (C1-C6) alkynyl group; R 2 represents H, -C(=O)(R a), -C(=O)(OR a), -C(=O)(R b), -P(=O)(OR b)(R c1), -P(=O)(R c1)(R c2), -C(=O)(OR d), -C(=O)(R h), -C(=O)(OR h) or -C(=O)(LR h); R 3a represents H or Re; R 3b represents H or its absence; R4 represents Rd or does not exist; R 5 represents H, -C(=O)(R a), -C(=O)(OR a), -C(=O)(R b), -C(=O)(OR d), -P(=O)(OR b)(R c1), -C(=O)(R h), -C(=O)(OR h) or -C(=O)(LR h); Each Ra represents a (C1-C25) alkyl group, which may be the same or different; Each Ra is replaced by an Rb, depending on the situation. Each Rb represents phenyl or cyclohexyl. Each Rb is substituted, depending on the case, with one to three independent groups selected from Rf, -CH2-OC(=O)(Rf), and -OC(=O)(Rf); Rc1 and Rc2 represent -NH-LC (=O) (OR f) and -NH-LC (=O) (OR g), respectively, and they may be the same or different; Each Rd represents independently or ; R e represents H, -C(=O)(R a), -C(=O)(OR a), -C(=O)-LOR f, -C(=O)-LOC(=O)(R f), -C(=O)-OLC(=O)(OR f), -C(=O)-LSC(=O)(R f), -C(=O)(R b), -C(=O)(OR b), -C(=O)-OLC(=O)(OR d), -C(=O)(R d), -C(=O)(R h) or -C(=O)(OR h); Each Rf independently represents a (C1-C18) alkyl group; Each L independently represents a (C1-C18) alkyl group; R g represents cyclohexyl; and Each Rh independently represents a steroid derivative or a bridging, spirocyclic, or fused polycyclic (C7-C18) carbon ring. The steroid derivatives are substituted with one to four independent groups selected from -OH and (C1-C12) alkyl groups, depending on the case; When R = 5, then R2 is not -P(=O)(OR b)(R c1) or -P(=O)(R c1)(R c2). When R is a 3a series H, R is a 3b series H, and R is a 5 series H, then R2 is not H, -C(=O)((C1-C5)alkyl) or -C(=O)(Z-butyl-Z'). Where Z represents bond, (C1-C10) alkyl, C(Rx)(Rz), Rx and Rz are independently selected from H, (C1-C6) alkyl, and (C6-C10) cycloalkyl. Each of Rx and Rz is independently, as appropriate, substituted with a (C1-C6) alkyl, syloxy, or (C1-C6) alkoxy group; and Z' represents H, (C1-C10)alkyl, or (C1-C10)alkoxy, and Z' is substituted with (C1-C6)alkyl, syloxy, or (C1-C6)alkoxy, depending on the situation; exist R3a series Re and R3b series H, Re series H or -C(=O)(O-(C1-C6)alkyl) or -C(=O)(C1-C25)alkyl, and When R is a 5-series H or -C (=O) (O-(C1-C25) alkyl), Then R2 is not -C (=O)(O-(C1-C25) alkyl); and exist R2 series H or -C (=O) (O-(C1-C10) alkyl), and R5 series -C(=O) (where applicable, substituted with a silylated alkyl group or a (C1-C6)alkyl group, substituted with a (C1-C18)alkyl group), -C(=O)- (where applicable, substituted with a (C1-C18)alkyl group, substituted with a cyclohexyl group), or -C(=O) (where applicable, substituted with a (C1-C6)alkyl group or -OC(=O) ((C1-C6)alkyl)phenyl group), when... Then Re is not (a) H, (b) -C(=O)(O-(C1-C10)alkyl) or (c) -C(=O)((C1-C15)alkyl); Or its pharmaceutically acceptable salts. This article also discloses formulas Ia and Ib. This article also discloses methods of manufacture and use. Implementation

[0004] Cross-reference to related applications

[0005] This application claims priority to U.S. Provisional Patent Application No. 62 / 992,733, filed March 20, 2020, entitled "PRODRUGS OF 4'-C-SUBSTITUTED-2-HALO-2'DEOXYADENOSINE NUCLEOSIDES AND METHODS OF MAKING AND USING THE SAME", the entire contents of which are incorporated herein by reference.

[0006] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments provided herein can be practiced without such details. The following description of several embodiments is made with the understanding that the invention should be regarded as an example of the claimed subject matter and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. The titles used throughout the invention are provided for convenience only and are not construed as limiting the scope of the claims in any way. Embodiments illustrated under any title may be combined with embodiments illustrated under any other title. I. Definition

[0007] The term "combined quantity" [Approximately] or " "[Approximately]" includes the stated value and has the meaning indicated by the context (e.g., including the degree of error related to the measurement of a particular quantity).

[0008] As used herein, the term "administering" or "administration" generally refers to administering a composition to a subject to deliver a drug (which is a composition or included in a composition) to a target site or site of intended treatment. Those skilled in the art will recognize various routes that can be used, where appropriate, to administer to a subject (e.g., a human). For example, in some embodiments, administration may be non-enteral. In some embodiments, administration may be performed by injection (e.g., intramuscular, intravenous, or subcutaneous). In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve administering a fixed number of doses. In some embodiments, administration may involve intermittent (e.g., multiple time-separated doses) and / or periodic (e.g., individual doses spaced at equal intervals) administration. In some embodiments, administration may involve continuous administration (e.g., infusion) for at least a selected time period.

[0009] " "[alkyl]" refers to hydrocarbons containing ordinary, secondary, or tertiary atoms. For example, alkyl groups can have 1 to 25 carbon atoms (i.e., (C1-C25)alkyl), 1 to 10 carbon atoms (i.e., (C1-C10)alkyl), 1 to 8 carbon atoms (i.e., (C1-C8)alkyl), or 1 to 6 carbon atoms (i.e., (C1-C6)alkyl). Suitable examples of alkyl groups include (but are not limited to) methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl ( [n]-Pr、 [positive]propyl, -CH2CH2CH3), 2-propyl ( [i]-Pr、 [Iso]propyl, -CH(CH3)2), 1-Butyl( [n]-Bu、 [positive] Butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl ( [i]-Bu、 [Iso]butyl, -CH2CH(CH3)2), 2-butyl( [s]-Bu、 [Second] Butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl ( [t]-Bu、 [Third] Butyl, -C(CH3)3), 1-pentyl ( [positive] pentyl, -CH 2CH 2CH 2CH 2CH 3), 2-pentyl (-CH(CH 3)CH 2CH 2CH 3), 3-pentyl (-CH(CH 2CH 3) 2), 2-methyl-2-butyl (-C(CH 3) 2CH 2CH 3), 3-methyl-2-butyl (-CH(CH 3)CH(CH 3) 2), 3-methyl-1-butyl (-CH 2CH 2CH(CH 3) 2), 2-methyl-1-butyl (-CH 2CH(CH 3)CH 2CH 3), 1-hexyl (-CH 2CH 2CH 2CH 2CH 2CH 3), 2-hexyl (-CH(CH 3)CH 2CH 2CH 2CH 3), 3-hexyl (-CH(CH 2CH 3)(CH 2CH 2CH) 3) 2-Methyl-2-pentyl (-C(CH 3) 2CH 2CH 2CH 3), 3-Methyl-2-pentyl (-CH(CH 3)CH(CH 3)CH 2CH 3), 4-Methyl-2-pentyl (-CH(CH 3)CH 2CH(CH 3) 2), 3-Methyl-3-pentyl (-C(CH 3)(CH 2CH 3) 2), 2-Methyl-3-pentyl (-CH(CH 2CH 3)CH(CH 3) 2), 2,3-Dimethyl-2-butyl (-C(CH 3) 2CH(CH 3) 2), 3,3-Dimethyl-2-butyl (-CH(CH 3)C(CH 3) 3 and octyl (-(CH 2) 7CH 3) "Alkyl" also refers to a saturated, branched, or straight-chain hydrocarbon group having two monovalent radical centers, which are derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. For example, an alkyl group may have 1 to 10 carbon atoms (i.e., (C1-C10)alkyl), 1 to 6 carbon atoms (i.e., (C1-C6)alkyl), or 1 to 3 carbon atoms (i.e., (C1-C3)alkyl). Typical alkyl groups include (but are not limited to) methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), and 1,3-propyl (-CH2CH2-). 2CH 2-), 1,4-butyl(-CH 2CH 2CH 2CH 2-) and the like.

[0010] The terminology used in this article is " [(C , 1-n , ) ] "[alkyl]" (also expressed as "(C1-Cn)alkyl", where n is an integer, alone or in combination with another group) refers to a non-cyclic, straight-chain or branched alkyl group containing 1 to n carbon atoms. "(C1-6)alkyl" includes (but is not limited to) methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (isopropyl), 1-methylpropyl (dibutyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tertiary butyl), pentyl, and hexyl. The abbreviations Me represent methyl; Et represents ethyl; Pr represents propyl; iPr represents 1-methylethyl; Bu represents butyl, and tBu represents 1,1-dimethylethyl.

[0011] " "[alkyl group]" (including those that are part of other groups) refers to a branched and unbranched divalent "alkyl group". As used herein, an alkyl group may have 1 to 25 carbon atoms (i.e., C1-25 alkyl group), 1 to 8 carbon atoms (i.e., C1-8 alkyl group), 1 to 6 carbon atoms (i.e., C1-6 alkyl group), or 1 to 4 carbon atoms (i.e., C1-4 alkyl group). Examples include: methylene, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, or 1,2-dimethylethyl. Unless otherwise stated, propyl and butyl are defined as including all possible isomers of the group discussed having the same number of carbon atoms. Thus, by way of example, propyl also includes 1-methylethyl and butyl includes 1-methylpropyl, 1,1-dimethylethyl, and 1,2-dimethylethyl.

[0012] " "[Alkenyl]" refers to a straight-chain or branched hydrocarbon containing normal, secondary, or tertiary carbon atoms, having at least one unsaturated site (i.e., a carbon-carbon sp2 double bond). For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., C2-C20 alkenyl), 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Suitable examples of alkenyl groups include (but are not limited to) ethylene or vinyl (-CH=(CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0013] The terminology used in this article is " [(C , 2-n , ) ] "[Alkenyl]" (where n is an integer, alone or in combination with another group) is intended to refer to an unsaturated, acyclic, straight-chain or branched group containing 2 to n carbon atoms, wherein at least two carbon atoms are bonded together by double bonds. Examples of such groups include (but are not limited to) vinyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl. Unless otherwise specified, the term "(C 2-n)alkenyl" is understood to encompass possible individual stereoisomers (including (but not limited to) (E) and (Z) isomers) and mixtures thereof. When (C 2-n)alkenyl is substituted, it should be understood that, unless otherwise specified, substitution may be made at any of its carbon atoms that originally had hydrogen atoms, thereby producing a chemically stable compound (e.g., as recognized by those skilled in the art).

[0014] " "[Alynyl]" refers to a straight-chain or branched hydrocarbon containing normal, secondary, or tertiary carbon atoms, having at least one unsaturated site (i.e., a carbon-carbon sp triple bond). For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C2-C20 alkynyl), 2 to 8 carbon atoms (i.e., C2-C8 alkynyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Suitable examples of alkynyl groups include (but are not limited to) acetylene groups (-C≡CH), propynyl groups (-CH2C≡CH), and the like.

[0015] The terminology used in this article is " [(C , 2-n , ) ] "[Alynyl]" (where n is an integer, alone or in combination with another group) is intended to refer to an unsaturated, acyclic, straight-chain or branched group containing 2 to n carbon atoms, wherein at least two carbon atoms are bonded together by a triple bond. Examples of such groups include (but are not limited to) ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. When the (C 2-n) ynyl group is substituted, it should be understood that, unless otherwise specified, substitution may be made on any of the carbon atoms that originally had hydrogen atoms, thereby producing a chemically stable compound (e.g., as recognized by those skilled in the art).

[0016] The terminology used in this article is " "[Antiviral agents]" refers to agents (compounds or biological agents) that effectively inhibit the formation and / or replication of viruses in humans, including (but not limited to) agents that interfere with the host or viral mechanisms required for the formation and / or replication of viruses in humans.

[0017] The terminology used in this article is " "[Aryl]" refers to an aromatic monocyclic, bicyclic, or polycyclic group. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl groups include phenyl groups or ortho, spiro, or bridging bicyclic or polycyclic groups (e.g., aryl groups fused to one or more aryl or carbocyclic rings) having about 9 to 14 atoms and at least one of them being aromatic rings. Such bicyclic or polycyclic groups may, where appropriate, be substituted with one or more (e.g., 1, 2, or 3) side oxygen groups on any carbocyclic portion of the bicyclic or polycyclic group. It should be understood that the connection point of the bicyclic or polycyclic group as defined above may be located at any position on the ring (including the aryl or carbocyclic portion of the ring). Typical aryl groups include (but are not limited to) phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracene, and the like.

[0018] " "[Arylalkyl]" refers to an alkyl group (i.e., the aryl-alkyl moiety) in which a hydrogen atom bonded to a carbon atom is replaced by an aryl group as described herein. The alkyl group of "arylalkyl" typically has 1 to 6 carbon atoms (i.e., aryl (C1-C6) alkyl). Arylalkyl groups include (but are not limited to) benzyl, 2-phenylethane-1-yl, 1-phenylpropane-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, and the like.

[0019] The terminology used in this article is " [aryl-(C, 1-n , ) ] "[alkyl-]" (where n is an integer, alone or in combination with another group) is intended to refer to an alkyl group having 1 to n carbon atoms as defined above, which is itself substituted with an aryl group as defined above. Examples of aryl-(C 1-n)alkyl- include (but are not limited to) phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl, and phenylpropyl. When aryl-(C 1-n)alkyl- is substituted, it should be understood that, unless otherwise specified, the substituent may be attached to its aryl or alkyl portion or both, thereby producing a chemically stable compound (e.g., as recognized by those skilled in the art).

[0020] the term" [Carbon ring] or " "[Carbocyclic]" refers to a saturated (i.e., cycloalkyl) or partially unsaturated (e.g., cycloalkenyl, cycloalkendienyl, etc.) ring having 3 to 7 carbon atoms in the form of a monocyclic or polycyclic system. In one embodiment, the carbocyclic system comprises a monocyclic ring (i.e., (C 3-C 6) carbocyclic ring) with 3 to 6 cyclic carbon atoms. The carbocyclic ring includes polycyclic carbocyclic rings having 7 to 12 carbon atoms (in bicyclic form) and up to about 20 carbon atoms (in polycyclic form), provided that the largest monocyclic ring of the polycyclic carbocyclic ring has 7 carbon atoms. The term "spirocyclic carbocyclic" refers to a carbocyclic system in which each ring of the system is linked to a single carbon atom (e.g., spiropentane, spiro[4.5]decane, spiro[4.5]decane, etc.). The term "fused carbocyclic ring" refers to a carbocyclic system in which each ring of the ring system is linked to two adjacent carbon atoms, such as a bicyclic [4,5], [5,5], [5,6], or [6,6] system, or a bicyclic [5,6] or [6,6] system with 9 or 10 ring atoms (e.g., decahydronaphthalene, norsabinane, norkaline). The term "bridging carbocyclic ring" refers to a carbocyclic system in which each ring of the ring system is linked to two non-adjacent carbon atoms (e.g., norcamphene, bicyclic [2.2.2]octane, etc.). The "carbocyclic ring" or "carbocyclic group" may be substituted with one or more (e.g., 1, 2, or 3) side oxygen groups, depending on the situation. Non-limiting examples of monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

[0021] " "[Carbocycloalkyl]" refers to an alkyl group (i.e., the carbocyclo-alkyl- moiety) in which a hydrogen atom bonded to a carbon atom is replaced by a carbocyclo group as described herein. The alkyl group of a "carbocycloalkyl" typically has 1 to 6 carbon atoms (i.e., carbocyclo(C1-C6)alkyl). Typical carbocycloalkyl groups include (but are not limited to) carbocyclo-CH2-, carbocyclo-CH(CH3)-, carbocyclo-CH2CH2-, 2-(carbocyclo)ethane-1-yl, and the like, wherein the "carbocyclo" moiety includes any of the aforementioned carbocyclo groups.

[0022] the term" "[Opposites]" refers to molecules that have a property of non-overlapping with their mirror counterparts, while the term "non-opposites" refers to molecules that can overlap with their mirror counterparts.

[0023] " "[Cycloalkyl]" refers to a non-aromatic hydrocarbon ring consisting of carbon and hydrogen atoms and having 3 to 15 carbon atoms, or in some embodiments 3 to 10 carbon atoms or 3 to 7 carbon atoms, which is saturated or partially unsaturated and connected to the rest of the molecule by single bonds. Cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, cycloheptenyl, and cyclooctyl.

[0024] The terminology used in this article is " [(C , 3-m , ) ] "[cycloalkyl]" (where m is an integer, alone or in combination with another group) refers to a cycloalkyl substituent containing 3 to m carbon atoms and includes (but is not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0025] The terminology used in this article is " [(C , 3-m , ) ] [cycloalkyl-(C, 1-n , ) ] "[alkyl-]" (where n and m are integers, alone or in combination with another group) refers to an alkyl group having 1 to n carbon atoms as defined above, which is itself substituted with a cycloalkyl group having 3 to m carbon atoms as defined above. Examples of (C 3-7)cycloalkyl-(C 1-6)alkyl- include (but are not limited to) cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclohexylethyl, and 2-cyclohexylethyl. When (C 3-m)cycloalkyl-(C 1-n)alkyl- is substituted, it should be understood that, unless otherwise specified, the substituent may be attached to its cycloalkyl or alkyl portion or both, thereby producing a chemically stable compound (e.g., as recognized by those skilled in the art).

[0026] As used in this article, the term " "[Combination therapy]" refers to situations where a subject is simultaneously exposed to two or more treatment or preventative regimens (e.g., two or more treatment or preventative agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, the regimens may be administered sequentially (for example, all "dose" of the first regimen may be administered before any dose of the second regimen); in some embodiments, the agents may be administered in an overlapping dosing regimen. In some embodiments, "administration" of combination therapy may involve administering one or more agents or methods in combination to a subject receiving other agents or methods. For clarity, combination therapy does not necessarily require the administration of individual agents together as a single composition (or even simultaneously), but in some embodiments, two or more agents or their active portions may be administered together as a combination composition or even as a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0027] As used in this article, the term " "[Comparable]" refers to two or more agents, entities, situations, or groups of conditions that may not be identical but are similar enough to allow for comparison, so that those skilled in the art should understand that reasonable conclusions can be drawn based on observed differences or similarities. In some embodiments, comparable conditions, situations, individuals, or groups of people are characterized by a plurality of substantially identical features and one or a few different features. In this context, those skilled in the art should understand the degree of similarity required for two or more such agents, entities, situations, or groups of conditions to be considered comparable in any given situation. For example, those skilled in the art should understand that situations, individuals, or groups of people are comparable when characterized by a sufficient number and type of substantially identical features to ensure that the differences in results or observed phenomena obtained under or using such different situations, individuals, or groups of people are caused by or indicate those different features.

[0028] Unless the context requires it, the term "" should be used throughout this invention and the scope of the patent application. The word "[comprise]" and its variations (such as "comprises" and "comprising") are interpreted as having an open, inclusive meaning, that is, as in "including (but not limited to)".

[0029] " "Diarrhetinic isomers" refer to stereoisomers that have two or more enantiomeric centers or axes and whose molecules are not mirror images of each other. Diarrhetinic isomers typically have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated in high-resolution analytical procedures such as electrophoresis and chromatography.

[0030] As used in this article, the term " "[Dosage Form]" refers to a physically discrete unit of an active agent (e.g., a therapeutic, preventative, or diagnostic agent) intended for administration to a subject. Typically, each unit contains a predetermined amount of the active agent. In some embodiments, this amount is suitable for administering a unit dose (or a portion thereof) according to a dosing regimen determined to be relevant to expected or beneficial outcomes when administered to the relevant population (i.e., using a preventative or therapeutic dosing regimen). Those skilled in the art will understand that the total amount of a composition or agent administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0031] Throughout this instruction manual, the word "one item" is used interchangeably with "an item". The reference to "[Example]" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment disclosed herein. Therefore, the phrases "in an embodiment" or "in one embodiment" appearing throughout this specification do not necessarily all refer to the same embodiment. In addition, a particular feature, structure, or characteristic may be combined in any suitable manner in one or more embodiments.

[0032] " "Enantiomers" refers to two stereoisomers of a compound that are mirror images of each other and do not overlap.

[0033] " [halogen] or " "[Halogen]" refers to bromine, chlorine, fluorine, or iodine.

[0034] The terminology used in this article is " [HIV] "[Replication inhibitor]" refers to a drug that can reduce or eliminate the ability of HIV to replicate in host cells (whether in vitro, in vitro, or in vivo).

[0035] The terminology used in this article is " [HBV] "[Replication inhibitor]" refers to a drug that can reduce or eliminate the ability of HBV to replicate in host cells (whether in vitro, in vitro, or in vivo).

[0036] " "[Mammals]" includes humans and livestock (such as laboratory animals and domestic pets (such as cats, dogs, pigs, cattle, sheep, goats, horses, rabbits) and non-livestock (such as wild animals) and the like.

[0037] " [As needed] or " "[As appropriate]" means that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, "substituted heterocyclic group as appropriate" means that the heterocyclic group may or may not be substituted, and the description includes both substituted and unsubstituted heterocyclic groups. It should be understood that when a variable is substituted (e.g., as described by the phrase "(C1-C6)alkyl (alone or as part of a group) substituted as appropriate"), the phrase means that the variable (C1-C6)alkyl can be substituted when it is alone and it can also be substituted when the variable "(C1-C6)alkyl" is part of a larger group (e.g., aryl(C1-C6)alkyl or -(C1-C6)alkyl-SO2-(C1-C6)alkyl-(C3-C7)carbocyclic group). Similarly, in the statement, other variables (e.g., (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, heteroaryl, heterocyclic, etc.) may also be substituted "alone or as part of a group".

[0038] The terminology used in this article is " "[Side oxygen group]" refers to an oxygen atom (=O) that acts as a substituent by being attached to a carbon atom via a double bond.

[0039] " "[Pharmaceutical acceptable excipients]" includes (but is not limited to) any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier or other pharmacologically inert substance that is formulated in combination with the pharmacologically active ingredient of a pharmaceutical composition and is compatible with the other components of the formulation, and is suitable for human or animal use without adverse toxicity, irritation, allergic reactions and the like.

[0040] The compound revealed in this article has the following characteristics: Examples of pharmaceutically acceptable salts include salts derived from suitable bases, such bases being alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX 4+ (where X is a C 1-4 alkyl group). Pharmaceutically acceptable salts having a nitrogen atom or an amino group include, for example, salts of the following acids: organic carboxylic acids, such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, butyric acid, camphoric acid, cinnamic acid, citric acid, digluconic acid, glutamic acid, glycolic acid, glycerophosphate, formic acid, hexanoic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, hydroxymaleic acid, malonic acid, malic acid, mandelic acid, and hydroxyethanesulfonic acid. Lacturonic acid, nicotinic acid, oxalic acid, pyruvic acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, neopentanoic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid, and succinic acid; organic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, tris(toluenesulfonic acid), benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonic acid; and inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and aminosulfonic acids. Pharmaceutically acceptable salts of compounds having a hydroxyl group include combinations of the compound's anion and a suitable cation (e.g., Na+ and N×4+, where X is independently selected from H or C1-4 alkyl groups).

[0041] For therapeutic applications, the salts of the active ingredients of the compounds disclosed herein are generally pharmaceutically acceptable, i.e., derived from physiologically acceptable acids or bases. However, salts of non-pharmaceutically acceptable acids or bases may also be used, for example, to prepare or purify the compounds of the examples disclosed herein. All salts (whether or not derived from physiologically acceptable acids or bases) are within the scope of the examples disclosed herein.

[0042] Metal salts are typically prepared by reacting a metal hydroxide with the compounds disclosed in the examples herein. Examples of metal salts prepared in this manner are salts containing Li+, Na+, and K+. The addition of a suitable metal compound can precipitate the less soluble metal salt from a solution of a more soluble salt.

[0043] Additionally, salts can be formed by adding certain organic and inorganic acids (e.g., HCl, HBr, H₂SO₄, H₃PO₄, or organic sulfonic acids) to a basic center (usually an amine). Finally, it should be understood that the compositions described herein comprise the compounds disclosed herein in both non-ionic and zwitterionic forms.

[0044] " "[Pharmaceutical Composition]" refers to the compounds disclosed in the embodiments herein and formulations of media commonly accepted in the industry for delivering bioactive compounds to mammals (e.g., humans). This media includes all pharmaceutically acceptable excipients.

[0045] As used in this article, the term " [prevention]( [preventing] and "[prevention]" refers to the administration of the compounds, compositions, or pharmaceutical salts of the present invention before or after human exposure to a virus, but before the onset of disease symptoms and / or before the virus is detected in the blood. In some embodiments, the term refers to the prevention of the onset of disease symptoms and / or the prevention of the virus reaching detectable levels in the blood. These terms also cover the administration of compounds or compositions of embodiments of the present invention disclosed herein before an individual is exposed to a virus (also referred to as pre-exposure prophylaxis or PrEP) to prevent HIV infection persistence (if an individual is exposed to the virus) and / or to prevent the establishment of permanent infection and / or to prevent the onset of disease symptoms and / or to prevent the virus reaching detectable levels in the blood. These terms include pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), and event-driven or "on-demand" prophylaxis. These terms also refer to the prevention of perinatal transmission of HIV from mother to infant by administration to the mother before delivery and to the infant in the first few days of life. The term also refers to the prevention of HIV transmission via blood transfusion.

[0046] " [snail] or " "[Spirocyclic]" refers to the aryl, carbocyclic, or heterocyclic structure described herein, which is linked to an existing ring structure in the compounds disclosed herein via a single atom. This single atom is shared by both the spirocyclic structure and existing ring structures. For example, the following bicyclic compounds include spirocyclopropane (i.e., a cyclopropane ring forming a spirocyclic ring with cyclohexane), spiro-1,3-dithiocyclopentane (i.e., a 1,3-dithiocyclopentane ring forming a spirocyclic ring with cycloheptane), and spirocyclopentene (i.e., a cyclopentene ring forming a spirocyclic ring with cyclohexene): .

[0047] the term" "[Stereoisomer]" refers to compounds having the same chemical composition but different spatial arrangements of atoms or groups. For example, "stereoisomer" refers to a compound composed of the same atoms bonded by the same bonds as another compound, but the two compounds have different three-dimensional structures that are not interchangeable. This invention considers various stereoisomers and mixtures thereof, including diastereomers, enantiomers, and the like. In any of the embodiments disclosed herein, the compounds disclosed herein may be in their stereoisomer forms.

[0048] The terminology used in this article is " "[Steroids]" (alone or in combination with another group) refers to a tetracyclic hydrocarbon ring (hexadecylhydro-1H-cyclopentan[a]phenanthrene) substituted with one to six independently selected groups from -OH and (C1-C12) alkyl groups, as appropriate; "Steroids" include (but are not limited to) cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, lithocholic acid, β-phytosterol, campesterol, cholesterol, stigmasterol, stigmasterol, campesterol, ergosterol, lupeol, cycloartenol.

[0049] As used in this article, the term " "[Subject]" refers to an organism, typically a mammal (e.g., a human). In some embodiments, the subject suffers from a relevant disease, condition, or symptom. In some embodiments, the human subject is an adult, adolescent, or child subject. In some embodiments, the subject is susceptible to a disease, condition, or symptom. In some embodiments, the subject exhibits one or more symptoms or characteristics of a disease, condition, or symptom. In some embodiments, the subject does not exhibit any symptoms or characteristics of a disease, condition, or symptom. In some embodiments, the subject is someone who has one or more characteristic characteristics of susceptibility or risk to a disease, condition, or symptom. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual who has received or has received a diagnosis and / or treatment and / or prevention.

[0050] As used in this article, " "Therapeutic effective amount" refers to the amount that produces the desired effect on the administerer. In some embodiments, the term "therapeutic effective amount" or "therapeutic effective dose" means an amount sufficient to treat a disease, condition, and / or symptom when administered to a population with or susceptible to the disease, condition, and / or symptom according to a therapeutic administration regimen. In some embodiments, a therapeutic effective amount is an amount that reduces the incidence and / or severity of one or more symptoms of a disease, condition, and / or symptom, stabilizes one or more characteristics, and / or delays the onset of the disease, condition, and / or symptom. Those skilled in the art will understand that the term "therapeutic effective amount" does not necessarily mean successful treatment in a particular individual. Rather, a therapeutic effective amount can be an amount that provides a specific expected pharmacological response in a large number of subjects when administered to patients who require the treatment. In some embodiments, reference to a therapeutic effective amount can refer to an amount measured in one or more specific tissues (e.g., tissues affected by the disease, condition, or symptom) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.). Those skilled in the art will understand that, in some embodiments, the therapeutically effective dose can be prepared and / or administered as a single dose. In some embodiments, the therapeutically effective dose can be prepared and / or administered in multiple doses, for example, as part of a dosing regimen.

[0051] Terminology related to diseases or symptoms [treat]( [treatment] or [treating] includes preventing the occurrence of disease or symptoms, suppressing disease or symptoms, eliminating disease or symptoms, and / or alleviating one or more symptoms of disease or symptoms.

[0052] Terminology related to the treatment of a patient's disease state [treat]( "[treating]" includes (i) suppressing or improving a patient's disease state, such as preventing or slowing its progression; or (ii) alleviating a patient's disease state, that is, resolving or curing the disease state. In the case of HIV, treatment includes reducing the HIV viral load in the patient.

[0053] The terminology used in this article is " [treat]( The term "treatment" refers to administering the compounds or compositions of this invention to alleviate or eliminate symptoms of HIV infection and / or reduce the viral load in patients. The term "treatment" also encompasses administering the compounds or compositions of this invention after an individual's exposure to the virus but before the onset of disease symptoms and / or before the virus is detected in the blood to prevent the onset of disease symptoms and / or to prevent the virus from reaching a detectable level in the blood. It also encompasses preventing perinatal transmission of HIV from mother to infant by administering the compounds or compositions of this invention to the mother before delivery and to the infant in the first few days of life.

[0054] The terminology used in this article is " [treat]( [treating] and The term "treatment" refers to administering the compounds or compositions disclosed herein to alleviate or eliminate one or more symptoms of HIV or HBV infection and / or reduce the viral load in a patient. In some embodiments, the terms "treating" also encompass administering the compounds or compositions disclosed herein after an individual's exposure to the virus but before the onset of disease symptoms and / or before the virus is detected in the blood to prevent the onset of disease symptoms and / or to prevent the virus from reaching a detectable level in the blood, and includes preventing, for example, perinatal transmission of HIV from mother to infant by administering the compounds or compositions disclosed herein to the mother before delivery and to the infant in the first few days of life. The terms "treating" also encompass administering the compounds or compositions disclosed herein before and after an individual's exposure to the virus. []

[0055] The embodiments disclosed herein are also intended to cover all pharmaceutically acceptable compounds of the formulas disclosed herein that are isotopically labeled (by using atoms with different atomic masses or mass numbers instead of one or more atoms). Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. In some embodiments, these radiolabeled compounds may be used to aid in the determination or measurement of the efficacy of the compound, for example, by characterizing the binding affinity of the site or pattern of action or to pharmacologically important sites. Some isotopically labeled compounds of the formulas disclosed herein (e.g., those incorporating radioisotopes) may be used in studies of drug and / or matrix tissue distribution. Radioactive isotopes tritium (i.e., 3H) and carbon-14 (i.e., 14C) are particularly suitable for this purpose because they are easy to incorporate and detect.

[0056] In some embodiments, the use of heavier isotopes such as deuterium (i.e., 2H) can provide certain therapeutic advantages due to their higher metabolic stability. For example, the in vivo half-life can be increased, or the dosage requirement can be reduced. Therefore, heavier isotopes may be preferred in some cases.

[0057] Substitution using positron-emitting isotopes (e.g., 11C, 18F, 15O, and 13N) can be used in positron emission tomography (PET) studies to examine acceptor occupancy. The isotopically labeled compounds disclosed herein can be prepared using techniques known to those skilled in the art, or by methods similar to those described in the examples below, using appropriate isotopically labeled reagents instead of the previously used unlabeled reagents.

[0058] The methods, compositions, kits, and articles provided herein use or include the compounds disclosed herein or their pharmaceutically acceptable salts, wherein one to n hydrogen atoms bonded to carbon atoms may be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium is a non-radioactive isotope of hydrogen. These compounds increase antimetabolism and can thus be used to increase the half-life of the compounds or their pharmaceutically acceptable salts when administered to mammals. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12):524-527 (1984). These compounds can be synthesized by means known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0059] The embodiments disclosed herein are also intended to cover in vivo metabolites of the disclosed compounds. EFdA is not intended to be included in the embodiments disclosed herein. These products can be generated from, for example, oxidation, reduction, hydrolysis, amination, esterification, and the like of the administered compound, and are primarily derived from enzymatic processes. Therefore, the embodiments disclosed herein include compounds produced by processes involving administration to mammals of the compounds of the embodiments disclosed herein for a time sufficient to produce their metabolites. These products are typically identified by administration to animals (e.g., rats, mice, guinea pigs, monkeys, or humans) of a detectable dose of the radiolabeled compounds of the embodiments disclosed herein, allowing sufficient time for metabolism and separation of their metabolites from urine, blood, or other biological samples.

[0060] The compounds disclosed in this embodiment, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thereby producing enantiomers, diastereomers, and other stereoisomers, which may be defined by absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. Unless specifically disclosed, this invention is intended to include all such possible isomers and their racemic, proportionate, and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers may be prepared using palmitic synthons or palmitic reagents, or resolved using methods such as chromatography and fractional crystallization. Techniques for preparing / separating individual enantiomers include palmitic synthesis from suitable optically pure precursors or resolution of racemic products (or racemic products of salts or derivatives) using, for example, palmitic high-performance liquid chromatography (HPLC). Where the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, and unless otherwise stated, such compounds are intended to include E and Z geometric isomers. Likewise, all tautomer forms are intended to be included. II. []compound

[0061] This document provides compounds for use as antiviral agents (anti-HIV agents in some embodiments), pharmaceutical compositions comprising such compounds in combination with one or more (e.g., two, three, or four) other therapeutic agents, and methods of using such compounds and compositions. All compound examples described herein include any pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers thereof.

[0062] In one embodiment, the formula () is provided [I]) Compound: (I) in The dashed line (----) together with the parallel solid line represents a double bond, depending on the situation; X represents halogen; R1 represents a (C1-C6) alkynyl group; R 2 represents H, -C(=O)(R a), -C(=O)(OR a), -C(=O)(R b), -P(=O)(OR b)(R c1), -P(=O)(R c1)(R c2), -C(=O)(OR d), -C(=O)(R h), -C(=O)(OR h) or -C(=O)(LR h); R 3a represents H or Re; R 3b represents H or its absence; R4 represents Rd or does not exist; R 5 represents H, -C(=O)(R a), -C(=O)(OR a), -C(=O)(R b), -C(=O)(OR d), -P(=O)(OR b)(R c1), -C(=O)(R h), -C(=O)(OR h) or -C(=O)(LR h); Each Ra represents a (C1-C25) alkyl group, which may be the same or different; Each Ra is replaced by an Rb, depending on the situation. Each Rb represents phenyl or cyclohexyl. Each Rb is substituted, depending on the case, with one to three independent groups selected from Rf, -CH2-OC(=O)(Rf), and -OC(=O)(Rf); Rc1 and Rc2 represent -NH-LC (=O) (OR f) and -NH-LC (=O) (OR g), respectively, and they may be the same or different; Each Rd represents independently or ; R e represents H, -C(=O)(R a), -C(=O)(OR a), -C(=O)-LOR f, -C(=O)-LOC(=O)(R f), -C(=O)-OLC(=O)(OR f), -C(=O)-LSC(=O)(R f), -C(=O)(R b), -C(=O)(OR b), -C(=O)-OLC(=O)(OR d), -C(=O)(R d), -C(=O)(R h) or -C(=O)(OR h); Each Rf independently represents a (C1-C18) alkyl group; Each L independently represents a (C1-C18) alkyl group; Rg represents cyclohexyl; and Each Rh independently represents a steroid derivative or a bridging, spirocyclic, or fused polycyclic (C7-C18) carbon ring. The steroid derivatives are substituted with one to four independent groups selected from -OH and (C1-C12) alkyl groups, depending on the case; When R = 5, then R2 is not -P(=O)(OR b)(R c1) or -P(=O)(R c1)(R c2). When R is a 3a series H, R is a 3b series H, and R is a 5 series H, then R2 is not H, -C(=O)((C1-C5)alkyl) or -C(=O)(Z-butyl-Z'). Where Z represents bond, (C1-C10) alkyl, C(Rx)(Rz), Rx and Rz are independently selected from H, (C1-C6) alkyl, and (C6-C10) cycloalkyl. Each of Rx and Rz is independently, as appropriate, substituted with a (C1-C6) alkyl, syloxy, or (C1-C6) alkoxy group; and Z' represents H, (C1-C10)alkyl, or (C1-C10)alkoxy, and Z' is substituted with (C1-C6)alkyl, syloxy, or (C1-C6)alkoxy, depending on the situation; exist R3a series Re and R3b series H, Re series H or -C(=O)(O-(C1-C6)alkyl) or -C(=O)(C1-C25)alkyl, and When R is a 5-series H or -C (=O) (O-(C1-C25) alkyl), Then R2 is not -C (=O)(O-(C1-C25) alkyl); and exist R2 series H or -C (=O) (O-(C1-C10) alkyl), and R5 series -C(=O) (where applicable, substituted with a silylated alkyl group or a (C1-C6)alkyl group, substituted with a (C1-C18)alkyl group), -C(=O)- (where applicable, substituted with a (C1-C18)alkyl group, substituted with a cyclohexyl group), or -C(=O) (where applicable, substituted with a (C1-C6)alkyl group or -OC(=O) ((C1-C6)alkyl)phenyl group), when... Then Re is not (a) H, (b) -C(=O)(O-(C1-C10)alkyl) or (c) -C(=O)((C1-C15)alkyl); Or a medicinally acceptable salt.

[0063] One of the following formulas ( [Ia]) compounds: (Ia) in X represents F or Cl; R 2 represents H, -C(=O)(R a), -C(=O)(R b) or -P(=O)(OR b)(R c1), R 3 represents H, -C (=O) (R a), or -C (=O) (OR a); R 5 represents H, -C (=O) (R a), or -P (=O) (OR b) (R c1); Each Ra independently represents a (C1-C25) alkyl group; Each Ra is independently replaced by an Rb, depending on the situation; Each Rb independently represents a phenyl group substituted with one to three independently selected groups from Rf and -OC(=O)(Rf), depending on the case; R c1 represents -NH-LC (=O) (OR g); Each Rf independently represents a (C1-C18) alkyl group; L represents (C1-C18) alkylene; and R g represents cyclohexyl; conditional system When R = 5, then R2 is not -P(=O)(OR b)(R c1). When R3 and R5 are H, then R2 is not H, -C(=O)((C1-C5)alkyl) or -C(=O)(Z-butyl-Z'). Where Z represents bond, (C1-C10) alkyl, C(Rx)(Rz), Rx and Rz are independently selected from H, (C1-C6) alkyl, and (C6-C10) cycloalkyl. Each of Rx and Rz is independently substituted, as appropriate, with (C1-C6)alkyl, syloxy, or (C1-C6)alkoxy groups; and Where Z' represents H, (C1-C10)alkyl or (C1-C10)alkoxy, and Z' may be substituted with (C1-C6)alkyl, syloxy or (C1-C6)alkoxy, depending on the situation; exist R 3 series H or -C(=O)(O-(C 1-C 6)alkyl) or -C(=O)(C 1-C 25)alkyl, and When R 5 series H, Then R2 is not -C (=O)(O-(C1-C25) alkyl); and exist R 2 series H, and When R5 series -C(=O)((C1-C18)alkyl), R3 is not H, -C(=O)(O-(C1-C10)alkyl) or -C(=O)((C1-C15)alkyl); Or a medicinally acceptable salt.

[0064] One of the following formulas ( [Ib]) compounds: ( [Ib]) in X represents F or Cl; R 2 represents -C(=O)(R a), R 5 represents H or -C (=O) (R a), Each Ra independently represents a (C1-C25) alkyl group substituted with an Rb, as appropriate; Each Rb independently represents a phenyl group substituted with one to three independently selected groups from -CH3 and -OC(=O)-CH3, as appropriate; and conditional system When R is a 5-series H, then R2 is neither -C(=O)(C1-C5 alkyl) nor -C(=O)(Z-butyl-Z'). Where Z represents bond, (C1-C10) alkyl, C(Rx)(Rz), Rx and Rz are independently selected from H and (C1-C6) alkyl groups; and Each of Rx and Rz is independently, as appropriate, substituted with a (C1-C6) alkyl, syloxy, or (C1-C6) alkoxy group; and Where Z' represents H, (C1-C10)alkyl or (C1-C10)alkoxy, and Z' may be substituted with (C1-C6)alkyl, syloxy or (C1-C6)alkoxy, depending on the situation; Or a medicinally acceptable salt.

[0065] The following statements apply to one or more of the formulas (formulas) revealed in this document. [I]、 [Ia] and [Ib]). X may be selected from halogens. In some embodiments, X-based Cl. In some embodiments, X-based F. In some embodiments, X-based Br. In some embodiments, X-based I.

[0066] R1 may be selected from (C1-C6) ynyl groups. In some embodiments, R1 is ethynyl. In some embodiments, R1 is propynyl. In some embodiments, R1 is butynyl. In some embodiments, R1 is pentyynyl. In some embodiments, R1 is hexynyl.

[0067] R2 can be selected from H, -C(=O)(R a), -C(=O)(OR a), -C(=O)(R b), -P(=O)(OR b)(R c1), -P(=O)(R c1)(R c2), -C(=O)(OR d), -C(=O)(R h), -C(=O)(OR h), and -C(=O)(LR h). Those skilled in the art will recognize the structures represented herein with this designation. For example, those skilled in the art will recognize that groups named -P(=O)(R c1)(R c2) and the like can also be represented as follows: .

[0068] Similarly, those skilled in this art will recognize that groups named -P(=O)(OR b)(R c1) and the like can also be represented as follows: .

[0069] Similarly, those skilled in this art will recognize that groups named -C(=O)(Ra) and similar groups can also be represented as follows: .

[0070] Similarly, those skilled in this technique will recognize that groups named -C(=O)(OR a) and the like can also be represented as follows: .

[0071] In some embodiments, R2-based H. In some embodiments, R2-based -C(=O)(Ra). In some embodiments, R2-based -C(=O)((C1-C25)alkyl). In some embodiments, R2-based -C(=O)((C1-C18)alkyl). In some embodiments, R2-based -C(=O)((C1-C12)alkyl). In some embodiments, R2-based -C(=O)((C1-C6)alkyl). In some embodiments, R2-based -C(=O)((C1-C4)alkyl). In some embodiments, R2-based -C(=O)(methyl). In some embodiments, R2-based -C(=O)(isopropyl). In some embodiments, R2-based -C(=O)(phenyl-substituted (C1-C4)alkyl). In some embodiments, R2-based -C(=O))(phenyl-substituted (C1-C4)alkyl), wherein the phenyl group is substituted with -CH3. In some embodiments, R2 is a -C(=O) (phenyl-substituted (C1-C4)alkyl), wherein the phenyl group is substituted with an acetoxy group. In some embodiments, R2 is a -C(=O) (phenyl-substituted (C1-C4)alkyl), wherein the phenyl group is substituted with a -CH3 group and an acetoxy group.

[0072] In some embodiments, R2-C(=O)(OR a). In some embodiments, R2-C(=O)((C1-C16)alkoxy). In some embodiments, R2-C(=O)((C1-C12)alkoxy).

[0073] In some embodiments, R2-C(=O)(Rb). In some embodiments, R2-C(=O)(aryl). In some embodiments, R2-C(=O)(cycloalkyl). In some embodiments, R2-C(=O)(phenyl substituted with (C1-C4)alkyl). In some embodiments, R2-C(=O)(phenyl). In some embodiments, R2-C(=O)(cyclohexyl). In some embodiments, R2-C(=O)(phenyl substituted with ester). In some embodiments, R2-C(=O)(cyclohexyl substituted with (C1-C4)alkyl). In some embodiments, R2-C(=O)(phenyl substituted with -CH2-C(=O)-(C1-C6)alkyl). In some embodiments, R2-C(=O)(phenyl substituted with -CH2-C(=O)-(C1-C4)alkyl). In some embodiments, R2-C(=O)(phenyl substituted with ester). In some embodiments, R2 is a C(=O) (ester-substituted phenyl), wherein the ester portion is a (C1-C16) alkyl ester, (C1-C12) alkyl ester, (C1-C6) alkyl ester, (C6-C12) alkyl ester, or (C12-C16) alkyl ester.

[0074] In some embodiments, R2 series - C(=O)(OR d). In some embodiments, R5 series - C(=O)(OR d), where Rd series... In some embodiments, R2 is a series of C(=O)(OR d), where Rd is a series of C(=O)(OR d). .

[0075] In some embodiments, R2-P(=O)(OR b)(R c1). In some embodiments, R2-P(=O)(O-phenyl)(R c1). In some embodiments, R2-P(=O)(O-phenyl)(-NH-CH(CH 3)-C(=O)-O-(C 1-C 6)alkyl). In some embodiments, R2-P(=O)(OR b)(-NH-CH(CH 3)-C(=O)-O-(C 1-C 6)alkyl). In some embodiments, R2-P(=O)(O-phenyl)(-NH-CH(CH 3)-C(=O)-O-(C 1-C 6)alkyl). In some embodiments, R2-P(=O)(OR b)(-NH-CH(CH 3)-C(=O)-O-(C 1-C 3)alkyl). In some embodiments, R2-P(=O)(O-phenyl)(-NH-CH(CH3)-C(=O)-O-(C1-C3)alkyl). In some embodiments, R2-P(=O)(O-phenyl)(-NH-CH(CH3)-C(=O)-O-(C4-C8)cycloalkyl). In some embodiments, R2-P(=O)(O-phenyl)(-NH-CH(CH3)-C(=O)-O-cyclohexyl). In some embodiments, R2-P(=O)(Rc1)(Rc2). In some embodiments, R2-P(=O)(-NH-CH(CH3)-C(=O)-O-(C1-C6)alkyl). In some embodiments, R2-P(=O)(-NH-CH(CH3)-C(=O)-O-(C1-C3)alkyl).

[0076] In some embodiments, R 2 comprises a phosphate residue. In some embodiments, R 2 comprises a phosphate derivative residue. In some embodiments, R 2 comprises a monophosphate residue. In some embodiments, R 2 comprises a diphosphate residue. In some embodiments, R 2 comprises a triphosphate residue. In some embodiments, R 2 comprises a phosphonate. In some embodiments, R 2 comprises a phosphate polyester. In some embodiments, R 2 comprises a phosphate diester. In some embodiments, R 2 comprises a phosphate triester. In some embodiments, R 2 comprises a phosphate amide. In some embodiments, R 2 comprises a phosphate monoamide. In some embodiments, R 2 comprises a phosphate diamide. In some embodiments, R 2 comprises a thiophosphate. In some embodiments, R 2 comprises a selenophosphate. In some embodiments, R 2 comprises a boron phosphate.

[0077] In some embodiments, R2-C(=O)(R h). In some embodiments, R2-C(=O)(OR h). In some embodiments, R2-C(=O)((C7-C10) carbide ring). In some embodiments, R2-C(=O)(bridged-bicyclic (C7-C10) carbide ring). In some embodiments, R2-C(=O)(bicyclic[2.2.2]octane). In some embodiments, R2-C(=O)(spiro-bicyclic (C7-C10) carbide ring). In some embodiments, R2-C(=O)(spiro[5.3]nonane). In some embodiments, R2-C(=O)(spiro[5.3]nonane). In some embodiments, R2-C(=O)(spiro[3.3]heptane). In some embodiments, R2-C(=O)(O-bridged-bicyclic (C7-C10) carbide ring). In some embodiments, R2-C(=O)(O-bicyclo[2.2.2]octane). In some embodiments, R2-C(=O)(O-spiro-bicyclo(C7-C10)carbocyclic). In some embodiments, R2-C(=O)(O-spiro[5.3]nonane). In some embodiments, R2-C(=O)(O-spiro[5.3]nonane. In some embodiments, R2-C(=O)(O-spiro[3.3]heptane.

[0078] In some embodiments, R2 series - C(=O)(LR h). In some embodiments, R2 series or .

[0079] In the formula In [I], R 3a can be selected from H and Re, and R 3b represents H or is absent. In some embodiments, R 3a is H. In some embodiments, R 3a is Re. In some embodiments, R 3b is H. In some embodiments, R 3b is absent. In some embodiments, R 3aR 3b is the same as R 2. In some embodiments, R 3aR 3b is different from R 2. In some embodiments, R 3aR 3b can be any of the possible substituents listed for R 2.

[0080] In some embodiments, R4 is absent. In some embodiments, R4 is Rd. In some embodiments, R4 is the same as R3a. In some embodiments, R4 is different from R3a. In some embodiments, R4 is the same as R3aR3b. In some embodiments, R4 is different from R3aR3b. In some embodiments, R4 may be any of the possible substituents listed for R3aR3b.

[0081] R5 can be H, -C(=O)(R a), -C(=O)(OR a), -C(=O)(R b), -C(=O)(OR d), -P(=O)(OR b)(R c1), -C(=O)(R h), -C(=O)(OR h), or -C(=O)(LR h). In some embodiments, R5 is the same as R 3a and R 3b. In some embodiments, R5 is the same as R 3a. In some embodiments, R5 is the same as R 2. In some embodiments, R5 is different from R 3a and R 3b. In some embodiments, R5 is different from R 3a. In some embodiments, R5 is different from R 2. In some embodiments, R5 can be any of the possible substituents listed for R 2. In some embodiments, R5 can be any of the possible substituents listed for R 3a and R 3b. In some embodiments, R5 can be any of the possible substituents listed for R 3a. In some embodiments, R2, R5, and R3a and R3b are the same. In some embodiments, R2, R5, and R3a are the same. In some embodiments, R2, R5, and R3a and R3b are not all the same. In some embodiments, R2, R5, and R3a are not all the same.

[0082] In some embodiments, R5-H. In some embodiments, R5-C(=O)(Ra). In some embodiments, R5-C(=O)(isopropyl). In some embodiments, R5-C(=O)(OR a). In some embodiments, R5-C(=O)(OR a). In some embodiments, R5-C(=O)((C1-C16)alkoxy). In some embodiments, R5-C(=O)((C1-C12)alkoxy). In some embodiments, R5-C(=O)((C1-C4)alkoxy). In some embodiments, R5-C(=O)(phenyl-substituted (C1-C4)alkyl), wherein the phenyl group is substituted with -CH3. In some embodiments, R5-C(=O)(phenyl-substituted (C1-C4)alkyl), wherein the phenyl group is substituted with acetoxy. In some embodiments, R 5-C (=O) (phenyl-substituted (C 1-C 4) alkyl), wherein the phenyl is substituted with -CH 3 and acetoxy.

[0083] In some embodiments, R5-C(=O)(Rb). In some embodiments, R5-C(=O)(phenyl substituted with (C1-C4)alkyl). In some embodiments, R5-C(=O)(cyclohexyl substituted with (C1-C4)alkyl). In some embodiments, R5-C(=O)(phenyl substituted with -CH2-C(=O)-(C1-C6)alkyl). In some embodiments, R5-C(=O)(phenyl substituted with -CH2-C(=O)-(C1-C4)alkyl).

[0084] In some embodiments, R5-C(=O)(OR d). In some embodiments, R5-C(=O)(OR d), where Rd is the system. In some embodiments, R5-C(=O)(OR d), where Rd is the system. .

[0085] In some embodiments, R5-P(=O)(OR b)(R c1). In some embodiments, R5-P(=O)(O-phenyl)(-NH-CH(CH 3)-C(=O)-O-(C 1-C 6)alkyl). In some embodiments, R5-P(=O)(OR b)(-NH-CH(CH 3)-C(=O)-O-(C 1-C 6)alkyl). In some embodiments, R5-P(=O)(O-phenyl)(-NH-CH(CH 3)-C(=O)-O-(C 1-C 6)alkyl). In some embodiments, R5-P(=O)(OR b)(-NH-CH(CH 3)-C(=O)-O-(C 1-C 3)alkyl). In some embodiments, R5-P(=O)(O-phenyl)(-NH-CH(CH 3)-C(=O)-O-(C 1-C 3)alkyl). In some embodiments, R 5-P(=O)(-NH-CH(CH 3)-C(=O)-O-(C 1-C 6)alkyl) 2. In some embodiments, R 5-P(=O)(-NH-CH(CH 3)-C(=O)-O-(C 1-C 3)alkyl) 2.

[0086] In some embodiments, R 5 comprises a phosphate residue. In some embodiments, R 5 comprises a phosphate derivative residue. In some embodiments, R 5 comprises a monophosphate residue. In some embodiments, R 5 comprises a diphosphate residue. In some embodiments, R 5 comprises a triphosphate residue. In some embodiments, R 5 comprises a phosphonate. In some embodiments, R 5 comprises a phosphate polyester. In some embodiments, R 5 comprises a phosphate diester. In some embodiments, R 5 comprises a phosphate triester. In some embodiments, R 5 comprises a phosphate amide. In some embodiments, R 5 comprises a phosphate monoamide. In some embodiments, R 5 comprises a phosphate diamide. In some embodiments, R 5 comprises a thiophosphate. In some embodiments, R 5 comprises a selenophosphate. In some embodiments, R 5 comprises a boron phosphate.

[0087] In some embodiments, R5-C(=O)(R h). In some embodiments, R5-C(=O)(OR h). In some embodiments, R5-C(=O)(LR h). In some embodiments, R5-C(=O)(O-spiro-bicyclic (C7-C10) carbide ring). In some embodiments, R5-C(=O)(O-spiro[5.3]nonane). In some embodiments, R5-C(=O)(O-spiro[5.3]nonane. In some embodiments, R5-C(=O)(O-spiro[3.3]heptane. In some embodiments, R5-C(=O)(O-spiro[5.3]nonane. In some embodiments, R5-C(=O)(bridged-bicyclic (C7-C10) carbide ring). In some embodiments, R5-C(=O)(bicyclic[2.2.2]octane). In some embodiments, R5-C(=O)(Biblio[2.2.2]octane. or .

[0088] In some embodiments, at least one Ra-based (C1-C25) alkyl group. In some embodiments, at least one Ra-based (C1-C18) alkyl group. In some embodiments, at least one Ra-based (C1-C6) alkyl group. In some embodiments, at least one Ra-based (C1-C4) alkyl group. In some embodiments, at least one Ra group is substituted with an Rb group.

[0089] In some embodiments, at least one Rb is a phenyl group. In some embodiments, at least one Rb is a cyclohexyl group. In some embodiments, at least one Rb is substituted with Rf. In some embodiments, at least one Rb is substituted with -CH2-OC(=O)(Rf). In some embodiments, at least one Rb is substituted with -OC(=O)(Rf). In some embodiments, at least one Rb is a phenyl group substituted with two independently selected Rf groups and one -OC(=O)(Rf). In some embodiments, at least one Rb is a phenyl group substituted with -CH3, -CH3, and -OC(=O)(CH3).

[0090] In some embodiments, at least one of Rc1 and Rc2 is -NH-LC (=O) (OR f). In some embodiments, at least one of Rc1 and Rc2 is -NH-LC (=O) (OR b). In some embodiments, Rc1 and Rc2 are the same. In some embodiments, Rc1 and Rc2 are different.

[0091] In some embodiments, at least one Rd comprises dioxane. In some embodiments, Rd comprises dioxane. In some embodiments, Rd comprises 1,3-dioxane. In some embodiments, Rd comprises dioxane substituted with one to three other groups selected from (C1-C6) alkyl and methyl groups. In some embodiments, Rd comprises 1,3-dioxane substituted with a methyl group. In some embodiments, Rd comprises 1,3-dioxane substituted with a methyl group and a methyl group. In some embodiments, Rd is a -(C1-C6)alkyl-dioxane. In some embodiments, Rd is a -CH2-dioxane. In some embodiments, Rd is a -CH2-dioxane, wherein the dioxane is substituted with a methyl group and a methyl group. In some embodiments, at least one Rd is a -(C1-C6)alkyl-dioxane. In some embodiments, at least one Rd system .

[0092] In some embodiments, Re is H. In some embodiments, Re is C(=O)(R a). In some embodiments, Re is C(=O)(OR a). In some embodiments, Re is C(=O)-LOR f. In some embodiments, Re is C(=O)-LOC(=O)(R f).

[0093] In some embodiments, Re-C(=O)-OLC(=O)(OR f). In some embodiments, Re-C(=O)-LSC(=O)(R f). In some embodiments, Re-C(=O)(R b). In some embodiments, Re-C(=O)(OR b).

[0094] In some embodiments, Re-C(=O)-OLC(=O)(OR d). In some embodiments, Re-C(=O)(R d). In some embodiments, Re-C(=O)(R h). In some embodiments, Re-C(=O)(OR h). In some embodiments, Re-C... or .

[0095] In some embodiments, Rf-based (C1-C6) alkyl groups. In some embodiments, Rf-based (C1-C3) alkyl groups.

[0096] In some embodiments, at least one L-series (C1-C6) alkylene group. In some embodiments, at least one L-series (C1-C4) alkylene group. In some embodiments, at least one Rh-series spiro-bicyclic (C7-C10) carbocyclic ring. In some embodiments, at least one Rh-series bridged-bicyclic (C7-C10) carbocyclic ring. In some embodiments, at least one Rh-series fused-polycyclic carbocyclic ring.

[0097] In some embodiments, at least one Rh is a steroid derivative, optionally substituted with one to four independently selected groups selected from -OH and (C1-C12) alkyl groups. In some embodiments, Rh comprises a bile acid conjugate. In some embodiments, Rh comprises a sterol.

[0098] In some embodiments, each -C(=O)(R h) is independently selected from and .

[0099] In some embodiments, -C(=O)(OR h) is a system Ry is independently selected from H, (C1-C8)alkyl and (C1-C8)alkenyl, and each Ry is independently substituted with (C1-C6)alkyl as appropriate.

[0100] In some embodiments, each -C(=O)(LR h) is independently selected from .

[0101] In some embodiments, the compounds disclosed herein have the following formula: Or its pharmaceutically acceptable salt. For the above-mentioned compounds with the language "X=F, Cl", this is intended to be equivalent to explicitly revealing each individual compound (the one with X=F and the other with X=Cl).

[0102] In some embodiments, compound systems or Or a medicinally acceptable salt.

[0103] In some embodiments, compound systems or Or a medicinally acceptable salt.

[0104] In some embodiments, compound systems or Or a medicinally acceptable salt. III. Pharmaceutical Compositions

[0105] In some embodiments, the present invention provides a pharmaceutical composition comprising the compounds of the present invention and pharmaceutically acceptable excipients.

[0106] In some embodiments, the pharmaceutical composition comprises one or more other therapeutic agents as more fully described below.

[0107] Pharmaceutical compositions comprising the compounds disclosed herein or their pharmaceutically acceptable salts may be prepared using one or more pharmaceutically acceptable excipients, which may be selected according to common practice. Tablets may contain excipients including gliding agents, fillers, binders, and the like. Aqueous compositions may be formulated as sterile and are generally isotonic when intended for delivery by means other than oral administration. In some embodiments, the composition may contain excipients such as those described in the following literature: Rowe et al., Handbook of Pharmaceutical Excipients, 6th edition, American Pharmacists Association, 2009. Excipients may include ascorbic acid and other antioxidants, chelating agents (e.g., EDTA), carbohydrates (e.g., dextrin), hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, and the like. In some embodiments, the composition is provided as a solid dosage form, including a solid oral dosage form.

[0108] The composition is suitable for various routes of administration, including oral administration. The composition can be presented in unit dosage forms and can be prepared by any method well known in the pharmaceutical industry. These methods include the step of combining an active ingredient (e.g., the compound of the present invention or its pharmaceutical salt) with one or more pharmaceutically acceptable excipients. The composition can be prepared by homogenizing and fully combining the active ingredient with a liquid excipient or a fine solid excipient, or both, and then shaping the product as desired. For techniques and formulations, see Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0109] Suitable for oral administration of the compositions described herein may be presented as discrete units (unit dosage forms) each containing a predetermined amount of active ingredient, including (but not limited to) capsules, sachets, or tablets. In one embodiment, the pharmaceutical composition is a tablet.

[0110] The pharmaceutical compositions disclosed herein comprise one or more of the compounds disclosed herein or pharmaceutically acceptable salts thereof, as well as pharmaceutically acceptable excipients and, where appropriate, other therapeutic agents. Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. For example, when intended for oral use, they may be prepared as tablets, lozenges, rhomboid tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more excipients (including sweeteners, flavoring agents, coloring agents, and preservatives) to provide a palatable formulation. Tablets containing a mixture of the active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated using known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained effect over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with waxes.

[0111] The amount of active ingredient that can be combined with an inert component to produce a dosage form may vary depending on the intended treatment subjects and the administration method. For example, in some embodiments, a dosage form for oral administration to humans may contain approximately 1 mg to 1000 mg of active material formulated with an appropriate and convenient amount of pharmaceutically acceptable excipients. In some embodiments, pharmaceutically acceptable excipients comprise approximately 5% to approximately 95% (by weight) of the total composition.

[0112] In some embodiments, in one variation, compositions comprising the compounds of the present invention or their pharmaceutically acceptable salts do not contain agents that affect the metabolic rate of the active ingredient. Therefore, it should be understood that, in one embodiment, compositions comprising the compounds of the present invention do not contain agents that affect (e.g., slow down, hinder, or delay) the metabolism of the compounds of the present invention or any other active ingredient administered separately, sequentially, or simultaneously with the compounds of the present invention. It should also be understood that, in one embodiment, the methods, kits, articles, and any of the like detailed herein do not contain agents that affect (e.g., slow down, hinder, or delay) the metabolism of the compounds of the present invention or any other active ingredient administered separately, sequentially, or simultaneously with the compounds of the present invention.

[0113] In some embodiments, the above-described pharmaceutical composition is used in humans or animals.

[0114] The present invention further includes the administration of the compound of the present invention as a single active ingredient in a pharmaceutically acceptable composition, the composition being prepared by conventional methods known in the art, for example by binding the active ingredient to a pharmaceutically acceptable therapeutically inert organic and / or inorganic carrier or excipient or by mixing therewith.

[0115] In one embodiment, this document provides for the use of the compounds of the present invention as a second or other active ingredient having a synergistic effect with other active ingredients in known pharmaceuticals, or as a compound of the present invention administered together with such pharmaceuticals.

[0116] The compounds of the present invention can also be used in prodrug form or in other suitable modified forms that release the active ingredient in vivo. IV. Treatment Methods HIV infection

[0117] This invention provides a method for treating and / or preventing human immunodeficiency virus (HIV) infection in a subject of need. In some embodiments, the method for treating and / or preventing HIV infection in a subject of need comprises administering to the subject the composition provided herein. In some embodiments, the method is used for treating and / or preventing HIV-1 infection. In some embodiments, the method is used for treating and / or preventing HIV-2 infection.

[0118] In some embodiments, a method of treating an HIV-infected subject in need includes administering the composition provided herein to the subject. In some of these embodiments, the subject is HIV-positive. In some of these embodiments, the subject has an unknown HIV status. In some of these embodiments, the subject is not HIV-negative.

[0119] In some embodiments, a method of preventing HIV infection in a subject of need comprises administering the composition provided herein to the subject. In some of these embodiments, the subject is HIV negative. In some embodiments, the subject is at risk of acquiring HIV infection.

[0120] In some embodiments, the present invention provides a composition for treating and / or preventing HIV infection in a subject.

[0121] In some embodiments, the present invention provides a composition for manufacturing a medicament for treating and / or preventing HIV infection in a subject.

[0122] In some embodiments, the present invention provides a method for treating and / or preventing HIV infection in a subject of need, comprising administering to the subject a combination therapy comprising the composition provided herein and one or more (e.g., one, two, three, one or two, or one to three) other therapeutic agents. In some embodiments, a method is provided for treating HIV infection in a human subject who is at risk of having such infection, comprising administering to the human subject a therapeutically effective amount of the composition disclosed herein and a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) other therapeutic agents. In some embodiments, the subject is receiving or has received one or more other therapeutic agents. In some embodiments, the other therapeutic agents are selected from the same class of therapeutic agents. In some embodiments, the other therapeutic agents are selected from different classes of therapeutic agents. In some embodiments, the other therapeutic agents are suitable for treating and / or preventing HIV infection. In some embodiments, the other therapeutic agents are not used for treating and / or preventing HIV infection.

[0123] In some embodiments, the combination therapy comprises administration of the composition provided herein and one, two, three, four, or more other therapeutic agents. In some embodiments, the combination therapy comprises administration of the composition provided herein and two other therapeutic agents. In some embodiments, the combination therapy comprises administration of the composition provided herein and three other therapeutic agents. In some embodiments, the combination therapy comprises administration of the composition provided herein and four other therapeutic agents.

[0124] Other therapeutic agents may be any other therapeutic agents disclosed herein. In some embodiments, other therapeutic agents are disclosed in the HIV combination therapy section of this document. In some embodiments, other therapeutic agents are disclosed in the HBV combination therapy section of this document.

[0125] In some embodiments, other therapeutic agents are anti-HIV agents. For example, in some embodiments, other therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosite) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, HIV Tat or Rev inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (e.g., CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (e.g., chimeric antigen receptor T cells (CAR-T) and modified T cell receptor (TCR)-T, autologous T cell therapy, modified B cells), latency reversal agents, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, protein 1 modulators containing COMM domains, HIV ribonuclease H inhibitors, reversal cyclic modulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines and combinations thereof.

[0126] In some embodiments, other therapeutic agents are selected from the group consisting of: combination drugs for the treatment and / or prevention of HIV infection, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosite) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins and combinations thereof.

[0127] In some embodiments, the other therapeutic agents are combination drugs for the treatment and / or prevention of HIV infection. Examples of combination drugs for the treatment and / or prevention of HIV infection include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (Tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobistat, and erlotinib); darunavir, tenofovir alafenamide hemifumarate hemifumarate, emtricitabine, and clobistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir elastatin and emtricitabine; tenofovir elastatin hemifumarate and emtricitabine; tenofovir elastatin hemifumarate, emtricitabine, and rilpivirine; tenofovir elastatin hemifumarate, emtricitabine, clobistat, and ertigvir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir and lamivudine); BIKTARVY (bictegravir + emtricitabine + tenofovir alafenamide), DOVATO, TRIZIVIR® (abacavir sulfate, zidovudine and lamivudine; ABC + AZT + 3TC); atazanavir and crobisstat;Atazanavir sulfate and cobistat; atazanavir sulfate and ritonavir; darunavir and cobistat; derogavir and rilpivirine; derogavir and rilpivirine hydrochloride; derogavir, abacavir sulfate and lamivudine; lamivudine, nevirapine and zidovudine; raltegravir and lamivudine; doravirine, lamivudine and tenofovir disoproxil fumarate; doravirine, lamivudine and tenofovir disoproxil fumarate. Disoproxil); Derogero + Lamivudine, Lamivudine + Abacavir + Zidovudine, Lamivudine + Abacavir, Lamivudine + Tenofovir Disoproxil Fumarate, Lamivudine + Zidovudine + Nevirapine, Lopinavir + Ritonavir, Lopinavir + Ritonavir + Abacavir + Lamivudine, Lopinavir + Ritonavir + Zidovudine + Lamivudine, Tenofovir + Lamivudine and Tenofovir Disoproxil Fumarate + Emtricitabine + Rilpivirine Hydrochloride, Lopinavir, Ritonavir, Zidovudine and Lamivudine; Cabotegravir + Rilpivirine; Elpida (elsulfavirine; VM-1500; VM-1500A).

[0128] In some embodiments, other therapeutic agents are medications used to treat and / or prevent HIV infection. Examples of other medications used to treat and / or prevent HIV infection include acemannan, alisporivir, BanLec, deferiprone, gamimune, metenkefalin, naltrexone, prolastin, and REP. 9. RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

[0129] In some embodiments, the other therapeutic agents are HIV protease inhibitors. Examples of HIV protease inhibitors include amprenavir, atazanavir, becanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, and TMC-310911.

[0130] In some embodiments, the other therapeutic agent is a reverse transcriptase inhibitor. The reverse transcriptase inhibitor may be a non-nucleoside / non-nucleotide inhibitor or a nucleoside / nucleotide inhibitor.

[0131] In some embodiments, other therapeutic agents are non-nucleoside or non-nucleotide reverse transcriptase inhibitors. Examples of HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and elfavirine (VM-1500).

[0132] In some embodiments, other therapeutic agents are nucleoside or nucleotide reverse transcriptase inhibitors. Examples of nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apritabine, censavudine, doxoproxil fumarate, elvucitabine, festinavir, and fosalvudine. tidoxil), CMX-157, dapoxil, doravirin, estradiol, OCR-5753, tenofovir disoproxil fumarate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-8583, VM-2500 and KP-1461.

[0133] In some embodiments, other therapeutic agents are HIV integrase inhibitors. Examples of HIV integrase inhibitors include erticagvir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, ginsenoside tricarboxylic acid, ginsenoside tricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin, tyramine phosphorylation inhibitor derivatives, quercetin, quercetin derivatives, retegvir, derogeivir, JTK-351, and bicroti. Bictegravir, AVX-15567, diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgin, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, and carboplatin.

[0134] In some embodiments, HIV integrase inhibitors are non-catalytic site (i.e., allolytic) integrase inhibitors (NCINIs). Examples of NCINIs include CX-05045, CX-05168, and CX-1442.

[0135] In some embodiments, the other therapeutic agents are HIV entry (fusion) inhibitors. Examples of HIV entry (fusion) inhibitors include cenoriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 linker inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

[0136] In some embodiments, other therapeutic agents are CCR5 inhibitors. Examples of CCR5 inhibitors include apraviroc, vicriviroc, maraviroc, cikviroc, leronlimab (PRO-140), adatabin (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, peptide C25P, TD-0680, and vMIP (Haimipu).

[0137] In some embodiments, the other therapeutic agents are gp41 inhibitors. Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biomodifiers, enfuvirtide biosimilars, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0138] In some embodiments, the other therapeutic agents are CD4 linker inhibitors. Examples of CD4 linker inhibitors include ibalizumab and CADA analogs.

[0139] In some embodiments, other therapeutic agents are gp120 inhibitors. Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38, banana lectin, bentonite-based nanoparticles, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0140] In some embodiments, the other therapeutic agents are CXCR4 inhibitors. Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0141] In some embodiments, the other therapeutic agent is an HIV maturation inhibitor. Examples of HIV maturation inhibitors include BMS-955176, GSK-3640254, and GSK-2838232.

[0142] In some embodiments, other therapeutic agents are latency reversal agents. Examples of latency reversal agents include TLR receptor (TLR) agonists (including TLR7 agonists, such as GS-9620), histoprotein deacetylase (HDAC) inhibitors, proteasome inhibitors (such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, IAP antagonists (apoptosis protein inhibitors, such as APG-1387, LBW-242), SMAC mimics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406), PMA, SAHA (suberanilohydroxamic acid or suberoyl, anilide, and hydroxamic acid). (acid), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion protein and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B and ubiquitin inhibitors (e.g. lagazole analogs, APH-0812 and GSK-343).

[0143] In some embodiments, other therapeutic agents are HDAC (e.g., histidine deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MTR; gene number: 9734) inhibitors. Examples of HDAC inhibitors include abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, and quisinostat. (JNJ-26481585), resminostat, ricolinostat, romidepsin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0144] In some embodiments, the other therapeutic agents are PKC inhibitors. Examples of PKC activators include indolinamide, prostratin, ingenol B, and DAG-lactone.

[0145] In some embodiments, other therapeutic agents are capsid inhibitors. Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-destructive compounds, HIV nucleocapsid p7 (NCp7) inhibitors (e.g., azodimethicone), HIV p24 capsid protein inhibitors, GS-6207, GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301 and the AVI-CAN1-15 series, as well as the compounds described in this patent (GSK WO2019 / 087016).

[0146] In some embodiments, other therapeutic agents are selected from one or more inhibitory immune checkpoint proteins or receptors, or blockers or inhibitors, and / or one or more stimulators, activators, or agonists of one or more stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune escape of infected cells. Activating or stimulating stimulating immune checkpoints can increase the effect of immune checkpoint inhibitors in the treatment of infections. In some embodiments, immune checkpoint proteins or receptors regulate T cell responses (as reviewed by Xu et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate NK cell responses (as reviewed by Davis et al., Semin Immunol. (2017) 31:64-75 and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0147] Examples of immune checkpoint proteins or receptors include (but are not limited to) CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2); protein 2 containing transmembrane and immunoglobulin domains (TMIGD2, CD28H); CD84 (LY9B, SLAMF5); CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); T cell activation inhibitory factor 1 containing V-set domains (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-related protein 2. (HHLA2, B7H7); T cell costimulatory factors (ICOS, CD278); T cell costimulatory ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated protein (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); Programmed cell death protein 1 (PDCD1, PD1, PD-1); Cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; NECTIN2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); Proteins containing PVR-associated immunoglobulin domains (PVRIG, CD112R); T-cell immune receptor with Ig and ITIM domains (TIGIT); Protein 4 containing T-cell immunoglobulin and mucin domains (TIMD4;TIM4); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); Galactoglobulin 9 (LGALS9); Lymphocyte activating protein 3 (LAG3, CD223); Signal transduction lymphocyte activating molecule family member 1 (SLAMF1, SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); Early retinoic acid transcript 1E (RAET1E; ULBP4); Early retinoic acid transcript 1G (RAET1G; ULBP5); Early retinoic acid transcript 1L (RAET1L; ULBP6); Lymphocyte activating protein 3 (CD223); killer cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail (KIR, CD158E1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

[0148] In some embodiments, other therapeutic agents are blockers or inhibitors of one or more T-cell suppressor immune checkpoint proteins or receptors. Examples of T-cell suppressor immune checkpoint proteins or receptors include (but are not limited to) CD274 (CD274, PDL1, PD-L1); programmed cell death protein 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death protein 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); T-cell activation inhibitory factor 1 containing a V-set domain (VTCN1, B7H4); V-se immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated proteins (BTLA)); proteins containing PVR-associated immunoglobulin domains (PVRIG, CD112R); T cell immune receptors with Ig and ITIM domains (TIGIT); lymphocyte activation protein 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactolectin 9 (LGALS9); killer cell immunoglobulin-like receptors (KIR, CD158E1) having three Ig domains and a long cytoplasmic tail 1; killer cell immunoglobulin-like receptors (KIR2DL1) having two Ig domains and a long cytoplasmic tail 1; killer cell immunoglobulin-like receptors (KIR2DL2) having two Ig domains and a long cytoplasmic tail 2; killer cell immunoglobulin-like receptors (KIR2DL3) having two Ig domains and a long cytoplasmic tail 3; and killer cell immunoglobulin-like receptors (KIR3DL1) having three Ig domains and a long cytoplasmic tail 1. In various embodiments, the agents as described herein are combined with one or more agonists or activators of one or more T cell-stimulating immune checkpoint proteins or receptors.Elucidating T-cell stimulating immune checkpoint proteins or receptors include (but are not limited to) CD27, CD70; CD40, CD40LG; inducible T-cell costimulatory factors (ICOS, CD278); inducible T-cell costimulatory factor ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; conjugative cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[0149] In some embodiments, the other therapeutic agents are blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Examples of NK cell inhibitory immune checkpoint proteins or receptors include (but are not limited to) killer cell immunoglobulin-like receptors (KIR, CD158E1) having three Ig domains and a long cytoplasmic tail 1; killer cell immunoglobulin-like receptors (KIR2DL1) having two Ig domains and a long cytoplasmic tail 1; killer cell immunoglobulin-like receptors (KIR2DL2) having two Ig domains and a long cytoplasmic tail 2; killer cell immunoglobulin-like receptors (KIR2DL3) having two Ig domains and a long cytoplasmic tail 3; killer cell immunoglobulin-like receptors (KIR3DL1) having three Ig domains and a long cytoplasmic tail 1; killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agents as described herein are combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Elucidating NK cell-stimulating immune checkpoint proteins or receptors include (but are not limited to) CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, for example, Davis et al., Semin Immunol. (2017) 31:64-75; Fang et al., Semin Immunol. (2017) 31:37-54; and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0150] In some embodiments, one or more immune checkpoint inhibitors comprise protein-based (e.g., antibody or fragment thereof or antibody mimic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors comprise small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitors of CD274 or PDCD1 are selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

[0151] In some embodiments, other therapeutic agents are CLTA4 inhibitors. Examples of CLTA4 inhibitors include ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), and MGD-019. (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4) and AK-104 (CTLA4 / PD-1).

[0152] In some embodiments, the other therapeutic agents are inhibitors of PD-L1 (CD274) or PD-1 (PDCD1). Examples of inhibitors of PD-L1 (CD274) or PD-1 (PDCD1) include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), and AK-103. (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 Dostarlimab, MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001, WBP-3155, KN-035, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752(CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1) and INBRX-105 (4-1BB / PDL1).

[0153] In some embodiments, the other therapeutic agent is an anti-TIGIT antibody. Examples of anti-TIGIT antibodies include BMS-986207, RG-6058, and AAGEN-1307.

[0154] In some embodiments, the other therapeutic agents are agonists of one or more members of the TNF receptor superfamily (TNFRSF), such as agonists of one or more of the following: TNFRSF1A (NCBI genotype: 7132), TNFRSF1B (NCBI genotype: 7133), TNFRSF4 (OX40, CD134; NCBI genotype: 7293), TNFRSF5 (CD40; NCBI genotype: 958), TNFRSF6 (FAS; NCBI genotype: 355), TNFRSF7 (CD27; NCBI genotype: 939), TNFRSF8 (CD30; NCBI genotype: 943), TNFRSF9 (4-1BB, CD137; NCBI genotype: 3604), TNFRSF10A (CD261, DR4, TRAILR1; NCBI genotype: 8797), TNFRSF10B (CD262, DR5, TRAILR2; NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3; NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4; NCBI gene ID: 8793), TNFRSF11A (CD265, RANK; NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266; NCBI gene ID: 51330), TNFRSF13B (CD267; NCBI gene ID: 23495), TNFRSF13C (CD268; NCBI gene ID: 115650), TNFRSF16 (NGFR, CD271; NCBI gene ID: 4804), TNFRSF17 (BCMA, CD269; NCBI gene ID: 608), TNFRSF18 (GITR, CD357; NCBI gene number: 8784), TNFRSF19 (NCBI gene number: 55504), TNFRSF21 (CD358, DR6; NCBI gene number: 27242) and TNFRSF25 (DR3; NCBI gene number: 8718).

[0155] In some embodiments, other therapeutic agents are anti-TNFRSF4 (OX40) antibodies. Examples of anti-TNFRSF4 (OX40) antibodies include MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0156] In some embodiments, the other therapeutic agent is an anti-TNFRSF5 (CD40) antibody. Examples of anti-TNFRSF5 (CD40) antibodies include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0157] In some embodiments, other therapeutic agents are anti-TNFRSF7 (CD27) antibodies. One example of an anti-TNFRSF7 (CD27) antibody is varlilumab (CDX-1127).

[0158] In some embodiments, other therapeutic agents are anti-TNFRSF9 (4-1BB, CD137) antibodies. Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies include urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106.

[0159] In some embodiments, the other therapeutic agent is an anti-TNFRSF18 (GITR) antibody. Examples of anti-TNFRSF18 (GITR) antibodies include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628.

[0160] In some embodiments, the other therapeutic agents are antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR). Such antibodies are described in, for example, WO2017096179 and WO2018089628.

[0161] In some embodiments, other therapeutic agents are bispecific NK cell adaptors (BiKE) or trispecific NK cell adaptors (TriKE) (e.g., without Fc) or bispecific antibodies (e.g., with Fc) targeting the following: NK cell activation receptors (e.g., CD16A), C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), native cytotoxic receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Suitablely, anti-CD16 binding bispecific molecules may or may not have an Fc. Elucidated bispecific NK cell adaptors include those targeting CD16 and one or more HIV-associated antigens. BiKE and TriKE are described, for example, in the following literature: Felices et al., Methods Mol Biol. (2016) 1441:333-346; Fang et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell adaptors (TRiKE) include OXS-3550 and CD16-IL-15-B7H3 TriKe.

[0162] In some embodiments, other therapeutic agents are inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene number: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranoquinone derivatives (SN-35837), remixstat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0163] In some embodiments, other therapeutic agents are agonists of TLR receptors (TLRs), such as agonists of TLR1 (NCBI genotype: 7096), TLR2 (NCBI genotype: 7097), TLR3 (NCBI genotype: 7098), TLR4 (NCBI genotype: 7099), TLR5 (NCBI genotype: 7100), TLR6 (NCBI genotype: 10333), TLR7 (NCBI genotype: 51284), TLR8 (NCBI genotype: 51311), TLR9 (NCBI genotype: 54106), and / or TLR10 (NCBI genotype: 81793).Example TLR7 agonists include AL-034, DSP-0509, GS-9620 (vesatolimod), LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, limoutop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and compounds disclosed in the following cases: US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249. (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). Examples of TLR7 / TLR8 agonists include NKTR-262, telratolimod, and BDB-001.Examples of TLR8 agonists include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, remiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and compounds disclosed in the following literature: US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics). Examples of TLR9 agonists include AST-008, cobitolimod, CMP-001, IMO-2055, IMO-2125, literimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotolimod, and PUL-042.Examples of TLR3 agonists include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonists include G-100 and GSK-1795091.

[0164] In some embodiments, other therapeutic agents are interferon gene-stimulating factor (STING) agonists or activators. Examples of STING receptor agonists or activators include ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP.

[0165] In some embodiments, other therapeutic agents are RIG-I modulators (e.g., RGT-100) or NOD2 modulators (e.g., SB-9200 and IR-103).

[0166] In some embodiments, other therapeutic agents are anti-TIM-3 antibodies, such as TSR-022, LY-3321367, MBG-453, and INCAGN-2390.

[0167] In some embodiments, other therapeutic agents are anti-LAG-3 (lymphocyte activation gene) antibodies, such as relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767, and INCAGN2385.

[0168] In some embodiments, other therapeutic agents are interleukin agonists, such as IL-2, IL-7, IL-15, IL-10, and IL-12 agonists; examples of IL-2 agonists include (e.g.) proleukin (aldesleukin, IL-2), pegylated IL-2 (e.g., NKTR-214), IL-2 modified variants (e.g., THOR-707), beempegaldesleukin, AIC-284, ALKS-4230, CUI-101, and Neo-2 / 15; examples of IL-15 agonists include (e.g.) ALT-803, NKTR-255 and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, and IL-15 synthorin. (PEGylated IL-15), P-22339 and IL-15-PD-1 fusion protein N-809; examples of IL-7 include CYT-107.

[0169] In some embodiments, other therapeutic agents are selected from the following immunotherapies: interferon α, interferon α-2b, interferon α-n3, pegylated interferon α, interferon γ, Flt3 agonists, gepon, normferon, pegylated interferon α-2a, pegylated interferon α-2b, and RPI-MN.

[0170] In some embodiments, the other therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, and puquitinib mesylate. mesylate), rigosertib, rigosertib sodium, sonolithib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-22 69577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV- 1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

[0171] In some embodiments, the other therapeutic agents are integrin α-4 / β-7 antagonists. Examples of integrin α-4 / β-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

[0172] In some embodiments, other therapeutic agents are HIV antibodies, bispecific antibodies, or "antibody-like" therapeutic proteins. Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bNAb (broadly neutralizing HIV-1 antibody), TMB-360 and antibodies targeting HIV gp120 or gp41, HIV-targeting antibody recruitment molecules, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-Nef single-domain antibodies, anti-Rev antibodies, camel-derived anti-CD18 antibodies, camel-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAb (PGT-121), elbalizumab, Imgro, and MB-66.

[0173] In some embodiments, other therapeutic agents are bNAbs. Examples include those described in U.S. Patents 8,673,307, 9,493,549, 9,783,594, WO2014 / 063059, WO2012 / 158948, WO2015 / 117008, PCT / US2015 / 41272, and WO2017 / 096221, including antibodies 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, 8ANC195, 8ANC196, 10-259, 10-303, 10-410, 10- 847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369 and 10-1074GM. Other examples include those described in the following literature: Klein et al., Nature, 492(7427): 118-22 (2012); Horwitz et al., Proc Natl Acad Sci USA, 110(41): 16538-43 (2013); Scheid et al., Science, 333: 1633-1637 (2011); Scheid et al., Nature, 458:636-640 (2009); Eroshkin et al., Nucleic Acids Res., 42 (database issue number): Dl 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (All bind to gp41 MPER); PG9, PG16, CH01-04 (all bind to V1V2-glycan), 2G12 (which binds to the outer domain glycan); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176 and 8ANC131 (all bind to CD4 binding sites).

[0174] In some embodiments, other therapeutic agents are broadly neutralizing antibodies, such as those described in, for example, the following: U.S. Patents 8,673,307, 9,493,549, 9,783,594 and WO 2012 / 154312, WO2012 / 158948, WO 2013 / 086533, WO 2013 / 142324, WO2014 / 063059, WO 2014 / 089152, WO 2015 / 048462, WO 2015 / 103549, WO 2015 / 117008, WO2016 / 014484, WO 2016 / 154003, WO 2016 / 196975, WO 2016 / 149710, WO2017 / 096221, WO 2017 / 133639, WO 2017 / 133640, the entire contents of which are incorporated herein by reference for all purposes. Other examples include those described in the following literature: Sajadi et al., Cell. (2018) 173(7):1783-1795; Sajadi et al., J Infect Dis. (2016) 213(1):156-64; Klein et al., Nature, 492(7427): 118-22 (2012); Horwitz et al., Proc Natl Acad Sci USA, 110(41): 16538-43 (2013); Scheid et al., Science, 333: 1633-1637 (2011); Scheid et al., Nature, 458:636-640 (2009); Eroshkin et al., Nucleic Acids Res., 42 (database issue number):Dl 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2 and LN01 (all MPERs bound to gp41).

[0175] Other antibodies that can be used as therapeutic agents include bavituximab, UB-421, BF520.1, CH01, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074-LS, GS-9722, DH411-2, and BG. 18. PGT145, PGT121, PGT-121.60, PGT-121.66, PGT122, PGT-123, PGT-124, PGT-125, PGT-126, PGT- 151. PGT-130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, MDX010 (Ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (Ipilimumab), VRC01, VRC-01-LS, A32, 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v4, IMC-HIV, iMabm36, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 3 54BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2 and LN01.

[0176] Examples of HIV bispecific and trispecific antibodies include MGD014, B12BiTe, TMB-bispecific, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, and 10E8v4 / PGT121-VRC01.

[0177] Examples of in vivo delivered bnab include, for example, AAV8-VRC07; VRC01, an anti-HIV antibody encoding mRNA; and modified B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301).

[0178] In some embodiments, the other therapeutic agent is a pharmacokinetic enhancer. Examples of pharmacokinetic enhancers include cobistat and ritonavir.

[0179] Examples of other therapeutic agents include compounds disclosed in the following cases: WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013 / 091096 (Boehringer Ingelheim).

[0180] In some embodiments, other therapeutic agents are HIV vaccines. Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors, such as Ad5, Ad26, or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus monkey (i.e., rhAd)), adeno-associated virus vector vaccines, and chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6). Pan7, Pan9), coxsackievirus-based vaccines, enterovirus-based vaccines, chimpanzee adenovirus vaccines, lentiviral vector-based vaccines, arenavirus vaccines (e.g., LCMV, Pichinde), two-segmented or three-segmented arenavirus-based vaccines, measles virus-based vaccines, flavivirus-based vaccines, tobacco mosaic virus-based vaccines, varicella-zoster virus-based vaccines, and human parainfluenza virus-based vaccines. (PIV3) vaccines; poxvirus-based vaccines (modified Vaccinia Ankara (MVA), orthopoxvirus-derived NYVAC, and avianpoxvirus-derived ALVAC (canarypoxvirus) strains); fowlpox virus-based vaccines; rod-shaped virus-based vaccines (e.g., VSV and marabavirus); recombinant human CMV (rhCMV)-based vaccines; alphavirus-based vaccines (e.g., Semliki forest virus, Venezuelan equine encephalitis virus, and Sindbis birus) (see Lauer, Clinical and Vaccine Immunology, 2017, DOI: 10.1128 / CVI.00298-16); therapeutic vaccines based on LNP-modulating mRNA; LNP-modulating self-replicating RNA / self-amplifying RNA vaccines.

[0181] Examples of vaccines include: rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multibranched DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[δ]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines (e.g., pseudoviral vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccines, HIV gag / pol / nef / env DNA vaccines, anti-TAT HIV vaccines, peptide-conjugated vaccines, dendritic cell vaccines (e.g., DermaVir), gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC Class II epitope heterozygous peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multi-branched Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x + romidesin, variant gp120 peptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60-mer-based vaccines, PD-201401, env (A,B,C,A / E) / gag (C) DNA vaccine, gp120 (A,B,C,A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvanted), HIV p24gag primiparous-booster plasmid DNA vaccine, arenavirus-based vaccines (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, UBI HIV gp120, mRNA-based preventative vaccines, and TBL-1203HI.

[0182] In some embodiments, other therapeutic agents include birth control agents (i.e., contraceptives). Examples of contraceptives include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, norethindrone, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norethindrone, norretynodrel, norgestimate, ormeloxifene, and segestersone acetate. Acetate), ulipristal acetate, and any combination thereof.

[0183] In some embodiments, the provided composition is combined with one, two, three, four or more other therapeutic agents selected from the following: ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (etigrazide, clobistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF + FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, clobistat, and etigrazide); BIKTARVY (Bicotilavir + Emtricitabine + Tenofovir Epramine); Adefovir; Adefovir Dipivoxel; Cobicistat; Emtricitabine; Tenofovir; Tenofovir Disoproxil Fumarate; Tenofovir Disoproxil Fumarate; Tenofovir Epramine; Tenofovir Hemifumarate; TRIUMEQ® (Drogavir, Abacavir, and Lamivudine); Drogavir, Abacavir Sulfate, and Lamivudine; Rettagvir; Rettagvir and Lamivudine; Maraviro; Enfuvirtide; ALUVIA® (KALETRA®; Lopinavir and Ritonavir); COMBIVIR® (Zidovudine and Lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; Abacavir Sulfate and Lamivudine; ABC+3TC); TRIZIVIR® (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and crombistarta; Atazanavir and crombistarta; Darunavir and crombistarta; Atazanavir; Atazanavir sulfate; Derogerovir; Eticagvir; Ritonavir; Atazanavir sulfate and Ritonavir; Darunavir; Lamivudine; Prosine; Furazanal Viagra; Furazanavir Calcium - Efaviren; Etravirine; Nafenavir; Nafenavir Mesylate; Interferon; Doxorinosine; Stavudine; Indinavir; Indinavir Sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir Mesylate; Aldehyde; Zaxitabine; Telanavir; Ampronavir; Dilaviridine; Dilaviridine Mesylate; Radha-108 (Lexiter); Lamivudine and Tenofovir Disoproxil Fumarate; Efaviren, Lamivudine and Tenofovir Disoproxil Fumarate; Aziphosphonate; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir Sulfate.

[0184] In some embodiments, the provided composition is combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors and HIV non-nucleoside reverse transcriptase inhibitors. In another specific embodiment, the pharmaceutical agent or pharmaceutical composition disclosed herein is combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors and HIV protease inhibitory compounds. In another embodiment, the pharmaceutical agent or pharmaceutical composition disclosed herein is combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, and pharmacokinetic enhancers. In some embodiments, the pharmaceutical agent or pharmaceutical composition disclosed herein is combined with at least one HIV nucleoside reverse transcriptase inhibitor, integrase inhibitor, and pharmacokinetic enhancer. In another embodiment, the pharmaceutical agent or pharmaceutical composition disclosed herein is combined with two HIV nucleoside or nucleotide reverse transcriptase inhibitors.

[0185] In some embodiments, the provided composition is combined with abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide fumarate.

[0186] In some embodiments, the provided composition is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0187] In some embodiments, the provided composition is combined with a first other therapeutic agent (selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate) and a second other therapeutic agent (selected from the group consisting of emtricitabine and lamivudine).

[0188] In some embodiments, the provided composition is combined with a first other therapeutic agent (selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate) and a second other therapeutic agent, wherein the second other therapeutic agent is emtricitabine.

[0189] In some embodiments, the provided composition is combined with a first other therapeutic agent (contraceptive) selected from the group consisting of: cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethylene estradiol, norethindrone, etogestene, L-5-methyltetrahydrofolate, levonorgestrel, linegestrel, medroxyprogesterone acetate, mestriol, mifepristone, misoprostol, normethyleneprogesterone acetate, methylprogesterone, norethindrone, isethindrone, norethindrone, olmexifen, sigmazoline acetate, ulipristal acetate, and any combination thereof.

[0190] In some embodiments, other therapeutic agents are gene therapy or cell therapy. Gene therapy and cell therapy include: gene modification to silence genes; gene-mediated methods of directly killing infected cells; designing infusions of immune cells to replace most of the patient's own immune system to enhance the immune response to infected cells, or activating the patient's own immune system to kill infected cells, or seeking out and killing infected cells; and modifying cell activity to further alter gene-mediated endogenous immune reactivity to infection. Examples of dendritic cell therapy include AGS-004. CCR5 gene editing agents include SB-728T. CCR5 gene inhibitors include Cal-1. In some embodiments, CD4-positive T cells expressing C34-CCR5 / C34-CXCR4 are co-administered with one or more multispecific antigen-binding molecules. In some embodiments, agents described herein are co-administered with autologous T-cell therapy transduced with AGT-103 or AAV-eCD4-Ig gene therapy.

[0191] In some embodiments, other therapeutic agents are gene-editing agents (e.g., HIV-targeting gene-editing agents). In some embodiments, gene editing systems are selected from the group consisting of: CRISPR / Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing nuclease complexes, and large-scale nuclease complexes. Elucidating HIV-targeting CRISPR / Cas9 systems include (but are not limited to) EBT-101.

[0192] In some embodiments, other therapeutic agents are CAR-T cell therapy. CAR-T cell therapy comprises a population of immune effector cells modified to express a chimeric antigen receptor (CAR), wherein the CAR contains an HIV antigen-binding domain. The HIV antigen comprises HIV mantle protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4 inducible binding site on gp120, an N-glycan on gp120, V2 of gp120, and a membrane adjoint region on gp41. The immune effector cell line is T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells may be autologous or allogeneic. Examples of HIV CAR-T include VC-CAR-T, CMV-N6-CART, anti-CD4 CART cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T cells, and autologous hematopoietic stem cells genetically modified to express CD4 CAR and C46 peptide.

[0193] In some embodiments, other therapeutic agents are TCR-T cell therapies. TCR-T cell therapies comprise TCR-T cells modified to target HIV-derived proteins present on the surface of virus-infected cells, such as ImmTAV.

[0194] In some embodiments, the antibody or antigen-binding fragment described herein is combined with a population of B cells that has been genetically modified to express a broadly neutralizing antibody (e.g., 3BNC117) (Hartweger et al., J. Exp. Med. 2019, 1301; Moffett et al., Sci. Immunol. 4, eaax0644 (2019), May 17, 2019). HBV infection

[0195] This invention provides a method for treating and / or preventing hepatitis B virus (HBV) infection in a subject of need. In some embodiments, the method for treating and / or preventing HBV infection in a subject of need comprises administering to the subject the composition provided herein.

[0196] In some embodiments, a method of treating HBV infection in a subject in need includes administering the composition provided herein to the subject.

[0197] In some embodiments, a method of preventing HBV infection in a subject of need comprises administering the composition provided herein to the subject. In some of these embodiments, the subject is at risk of acquiring HBV infection.

[0198] In some embodiments, the present invention provides a composition for treating and / or preventing HBV infection in a subject.

[0199] In some embodiments, the present invention provides a composition for manufacturing a medicament for treating and / or preventing HBV infection in a subject.

[0200] In some embodiments, the present invention provides a method for treating and / or preventing HBV infection in a subject of need, comprising administering to the subject a combination therapy comprising the composition provided herein and one or more other therapeutic agents. In some embodiments, the subject is receiving or has received one or more other therapeutic agents. In some embodiments, the other therapeutic agents are selected from the same class of therapeutic agents. In some embodiments, the other therapeutic agents are selected from different classes of therapeutic agents. In some embodiments, the other therapeutic agents are used for treating and / or preventing HBV infection. In some embodiments, the other therapeutic agents are not used for treating and / or preventing HBV infection.

[0201] In some embodiments, the present invention provides a method for treating HBV infection comprising administering to a subject in need a therapeutically effective amount of the composition disclosed herein and a combination of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents suitable for treating HBV infection.

[0202] In some embodiments, the compositions disclosed herein are combined with one, two, three, four, or more other therapeutic agents. In some embodiments, the compositions disclosed herein are combined with two other therapeutic agents. In some embodiments, the compositions disclosed herein are combined with three other therapeutic agents. In some embodiments, the compositions disclosed herein are combined with four other therapeutic agents. The one, two, three, four, or more other therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or may be selected from different classes of therapeutic agents.

[0203] The compositions described herein may be used or combined with one or more of the following: chemotherapeutic agents, immunomodulators, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies and "antibody-like" therapeutic proteins (e.g., DARTs®, Duobodies®, Bits®, XmAbs®, TandAbs®, Fab derivatives), antibody-drug conjugates (ADCs), gene modifiers or gene editing agents (e.g., CRISPR Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (e.g., CAR-T (chimeric antigen receptor T cells) and TCR-T (modified T cell receptor) agents) or any combination thereof.

[0204] In some embodiments, other therapeutic agents may be anti-HBV agents. For example, other therapeutic agents may be selected from the group consisting of: HBV combination drugs, other drugs for treating HBV, 3-dioxanone (IDO) inhibitors, antisense oligonucleotides targeting viral mRNA, apolipoprotein A1 modulators, arginase inhibitors, B- and T-lymphocyte attenuation protein inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, compounds targeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg), covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytokines, and cytotoxic T-lymphocyte-associated protein 4 (CLP-4). (ipi4) inhibitors, DNA polymerase inhibitors, endonuclease modifiers, postgenetic modifiers, farnesoid X receptor agonists, gene modifiers or editing agents, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV antibodies, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBV RNase inhibitors, HBV vaccines, HBV virus entry inhibitors, HBx inhibitors, hepatitis B mantle protein modifiers, hepatitis B mantle protein stimulators, hepatitis B structural protein modifiers, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus e antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitors, HIV-1 reverse transcriptase inhibitors, hyaluronidase inhibitors, IAP inhibitors, IL-2 agonists, IL-7 agonists, immunoglobulin agonists, immunoglobulin G modifiers, immunomodulators, indoleamine-2, ribonucleotide reductase inhibitors, interferon agonists, interferon alpha. Interferon α ligand, interferon α 2 ligand, interferon α 5 ligand modulator, interferon α ligand, interferon α ligand modulator, interferon α receptor ligand, interferon β ligand, interferon ligand, interferon receptor modulator, interleukin-2 ligand, IPI4 inhibitor, lysine demethylase inhibitor, histone demethylase inhibitor, KDM5 inhibitor, KDM1 inhibitor, killer cell lectin-like receptor subfamily G member 1 inhibitor, lymphocyte-activated gene 3 inhibitor, lymphotoxin β receptor activator, microRNA(miRNA) gene therapy agents, Axl modulators, B7-H3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, CD70 modulators, GITR modulators, HEVEM modulators, ICOS modulators, Mer modulators, NKG2A modulators, NKG2D modulators, OX40 modulators, SIRPα modulators, TIGIT modulators, Tim-4 modulators, Tyro modulators, Na+-taurocholic acid cotransporter (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon λ, peptidylprolyl isomerase inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, recombinant scavenger receptor A (SRA) protein, recombinant thymosin α-1, retinoic acid-inducible gene 1 stimulator, reverse transcriptase inhibitor, ribonuclease inhibitor, RNA DNA polymerase inhibitor, short interfering RNA (siRNA), short synthetic hairpin RNA (sshRNA), SLC10A1 gene inhibitor, SMAC mimic, Src tyrosine kinase inhibitor, interferon gene stimulating protein (STING) agonist, NOD1 stimulator, T cell surface glycoprotein CD28 inhibitor, T cell surface glycoprotein CD8 regulator, thymosin agonist, thymosin α-1 ligand, Tim-3 inhibitor, TLR-3 agonist, TLR-7 agonist, TLR-9 agonist, TLR9 gene stimulator, TLR receptor (TLR) regulator, viral ribonucleotide reductase inhibitor, zinc finger nuclease or synthetic nuclease (TALEN) and combinations thereof.

[0205] In some embodiments, the provided composition is combined with one, two, three, four or more other therapeutic agents selected from: HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, TLR receptor (TLR) modulators, interferon α receptor ligands, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV virus entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi intranuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, and covalently closed circular DNA. (cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein regulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin α-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, and other HBV drugs.

[0206] In some embodiments, the other therapeutic agents are HBV combination drugs. Examples of HBV combination drugs include TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine and PEG-IFN-α; ABX-203 adefovir and PEG-IFNα; and INO-1800 (INO-9112 and RG7944).

[0207] In some embodiments, the other therapeutic agent is another HBV drug.Examples of other drugs used to treat HBV infection include alpha-hydroxytropolone, amdoxovir, β-hydroxycytosine nucleoside, AL-034, CCC-0975, evitabine, ezetimibe, cyclosporine A, gentiopicrin, gentiopicroside, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligosaccharides, mivotilate, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, and Y-101 (Ti Fen). Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IPBB-006IA, Hepuyinfen, DasKloster 0014-01、ISA-204、Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551 and ZH-2N, as disclosed in US20150210682, (Roche), US 2016 / 0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 The compounds listed in (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche) and US2015031687A (Roche).

[0208] In some embodiments, other therapeutic agents are HBV vaccines. In some embodiments, the HBV vaccine is a preventative HBV vaccine. Examples of preventative HBV vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D / T / P / HBV / M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B preventative vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenula polymorpha yeast, intramuscular, Hualan Biological Products). Engineering), recombinant hepatitis B surface antigen vaccine, Bimmugen, Eufravac, Eutravac, Anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa and DTaP-rHB-Hib vaccine.

[0209] In some embodiments, the HBV vaccine is a therapeutic HBV vaccine. Examples of therapeutic HBV vaccines include HBsAG-HBIG complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (εPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500, HBVax, im / TriGrid / antigen vaccine, Mega-CD40L adjuvanted vaccine, HepB-v, RG7944 (INO-1800), and recombinant VLP-based therapeutic vaccines (HBV infection, VLP). Biotech), AdTG-17909, AdTG-17910, AdTG-18202, ChronVac-B, TG-1050 and Lm HBV.

[0210] In some embodiments, other therapeutic agents are HBV DNA polymerase inhibitors. Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, besifovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), pradefovir, clevudine, ribavirin, and lamivudine (EPIVIR-HBV). ®), phosphine azide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil fumarate aspartate, tenofovir disoproxil fumarate orotate, and HS-10234.

[0211] In some embodiments, the other therapeutic agents are immunomodulators. Examples of immunomodulators include rapamod, imidol hydrochloride, ingaron, dermaVir, hydroxychloroquine sulfate tablets (hydroxychloroquine), prazolam, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-12, INO-9112, polymeric polyethyleneimine (PEI), guapentin, VGV-1, MOR-22, BMS-936559, RO-7011785, RO-6871765, AIC-649, and IR-103.

[0212] In some embodiments, other therapeutic agents are TLR receptor (TLR) modulators. TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13.

[0213] In some embodiments, the TLR modifier is a TLR3 modifier. Examples of TLR3 modifiers include rapamod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, GS-9688, and ND-1.1.

[0214] In some embodiments, the TLR modifier is a TLR7 modifier. Examples of TLR7 modifiers include GS-9620, GSK-2245035, imiquimod, remiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, limoutop, TMX-30X, TMX-202, RG-7863, RG-7795, RG-7854 and compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences) and US20090047249 (Gilead Sciences).

[0215] In some embodiments, the TLR regulator is a TLR8 regulator. Examples of TLR8 modulators include motomodil, remiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and those disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), and US20100029585 (Ventirx). Compounds listed in US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics).

[0216] In some embodiments, the TLR modifier is a TLR9 modifier. Examples of TLR9 modifiers include BB-001, BB-006, CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, Atomomod, DIMS-9054, DV-1079, DV-1179, AZD-1419, Lefemod (MGN-1703), Litamod, and CYT-003-QbG10.

[0217] In some embodiments, other therapeutic agents are interferon α receptor ligands. Examples of interferon α receptor ligands include interferon α-2b (INTRON A®), pegylated interferon α-2a (PEGASYS®), pegylated interferon α-1b, interferon α-1b (HAPGEN®), Veldona, Infradure, Roferon-A, YPEG-interferon α-2a (YPEG-rhIFNα-2a), P-1101, Algeron, Alfarona, Ingaron (interferon γ), rSIFN-co (recombinant high-efficiency complex interferon), Ypeg interferon α-2b (YPEG-rhIFNα-2b), MOR-22, pegylated interferon α-2b (PEG-INTRON®), Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon α-n1 (HUMOFERON®), and interferon β-1a (AVONEX). ®), Shaferon, Interferon α-2b (Axxo), Alfaferone, Interferon α-2b (BioGeneric Pharma), Interferon-α 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, PDferon-B, Interferon α-2b (IFN, Laboratorios Bioprofarma), Interferon α 2b, Kalferon, Pegnano, Feronsure, PegiHep, Interferon α 2b (Zydus-Cadila), Interferon α 2a, Optipeg A, Realfa 2B, Reliferon, Interferon α-2b (Amega), Interferon α-2b (Virchow), Ropeg Interferon α-2b, rHSA-IFNα-2a (Recombinant Human Serum Albumin Interferon α 2a Fusion Protein), rHSA-IFNα 2b. Recombinant human interferon α-(1b, 2a,2b) Pegylated interferon α-2b (Amega), pegylated interferon α-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon α-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFNα-2b, SFR-9216, and Interapo (Interapa).

[0218] In some embodiments, the other therapeutic agent is a hyaluronidase inhibitor. An example of a hyaluronidase inhibitor is astodrimer.

[0219] In some embodiments, the other therapeutic agents are hepatitis B surface antigen (HBsAg) inhibitors. Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031, REP-006, and REP-9AC′. One example of an HBsAg secretion inhibitor is BM601.

[0220] In some embodiments, the other therapeutic agents are cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors. Examples of cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilimumab, belapatacept, PSI-001, PRS-010, Probody mAbs, trimemumab, and JHL-1155.

[0221] In some embodiments, the other therapeutic agents are cyclophilin inhibitors. Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and compounds disclosed in US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and US20130344029 (Gilead Sciences).

[0222] In some embodiments, the other therapeutic agent is an HBV entry inhibitor. One example of an HBV entry inhibitor is Myrcludex B.

[0223] In some embodiments, other therapeutic agents are antisense oligonucleotides that target viral mRNA. Examples of antisense oligonucleotides that target viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, and RG-6004.

[0224] In some embodiments, the other therapeutic agent is a short interfering RNA (siRNA). Examples of siRNAs include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, and ARB-1467.

[0225] In some embodiments, the other therapeutic agent is a DNA-guided RNA interference (ddRNAi) agent. An example of ddRNAi is BB-HB-331.

[0226] In some embodiments, the other therapeutic agents are endonuclease modulators. One example of an endonuclease modulator is PGN-514.

[0227] In some embodiments, the other therapeutic agent is a ribonucleotide reductase inhibitor. An example of a ribonucleotide reductase inhibitor is Trimidox.

[0228] In some embodiments, the other therapeutic agent is an HBV E antigen inhibitor. One example of an HBV E antigen inhibitor is wogonin.

[0229] In some embodiments, the other therapeutic agent is a covalently closed circular DNA (cccDNA) inhibitor. Examples of cccDNA inhibitors include BSBI-25 and CHR-101.

[0230] In some embodiments, the other therapeutic agents are farnesol x receptor agonists. An example of a farnesol x receptor agonist is EYP-001.

[0231] In some embodiments, other therapeutic agents are HBV antibodies. Examples of HBV antibodies targeting the surface antigen of hepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and whole-human monoclonal antibody therapy (hepatitis B virus infection, Humabs BioMed). Examples of HBV antibodies (including monoclonal and polyclonal antibodies) include Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088). Whole-human monoclonal antibodies, such as HBC-34.

[0232] In some embodiments, other therapeutic agents are CCR2 chemokine antagonists. One example of a CCR2 chemokine antagonist is propagermanium.

[0233] In some embodiments, the other therapeutic agent is a thymosin agonist. Examples of thymosin agonists include thymalfasin and recombinant thymosin α1 (GeneScience).

[0234] In some embodiments, other therapeutic agents are cytokines. Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and celmoleukin.

[0235] In some embodiments, the other therapeutic agents are nucleoprotein modulators. In some embodiments, the nucleoprotein modulators are HBV core or capsid protein inhibitors. Examples of nucleoprotein modulators include AB-423, AT-130, GLS4, NVR-1221, NVR-3778, BAY 41-4109, morphothiadine mesilate, JNJ-379, RG-7907, ABI-H0731, ABI-H2158, and DVR-23. Examples of capsid inhibitors include those disclosed in US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015 / 059212 (Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen), and WO2014184350. (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652 (Novira), US20150259324 (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche).

[0236] In some embodiments, the other therapeutic agents are retinoic acid-induced gene 1 stimulators. Examples of retinoic acid-induced gene 1 stimulators include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, ORI-7170, and RGT-100.

[0237] In some embodiments, the other therapeutic agent is a NOD2 stimulant. An example of a NOD2 stimulant is SB-9200.

[0238] In some embodiments, other therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. Examples of PI3K inhibitors include ederaris, ACP-319, AZD-8186, AZD-8835, bupparis, CDZ-173, CLR-457, picococci, neratinib, regoracitinib, regoracitinib sodium, EN-3342, TGR-1202, apecilpine, duveris, IPI-549, UCB-5857, tasicoxib, XL-765, godatoris, ME-401, VS-5584, coupannis, CAI orotate, perifoxine, RG-7666, GSK-2636771, DS-7423, panulisexine, and GSK-22. 69557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, Piracetam, BAY-1082439, Proquintinib Mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, Sonicoxib, LY-3023414, SAR-260301, TAK-117, HMPL-689, Tenalisib, Voxtalisib, and CLR-1401.

[0239] In some embodiments, the other therapeutic agents are inhibitors of the indoleamine-2,3-dioxygenase (IDO) pathway. Examples of IDO inhibitors include epalrestat (INCB24360), remixstat (4SC-201), insimod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028, GBV-1012, NKTR-218, and compounds disclosed in US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), and WO2015188085 (Flexus Biosciences, Inc.).

[0240] In some embodiments, the other therapeutic agents are PD-1 inhibitors. Examples of PD-1 inhibitors include nivorumab, pembrolizumab, pilizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110, and mDX-400.

[0241] In some embodiments, the other therapeutic agents are PD-L1 inhibitors. Examples of PD-L1 inhibitors include atezolizumab, avirumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX-072, and BMS-936559.

[0242] In some embodiments, the provided composition is combined with compounds such as those disclosed in the following cases: WO2018026971, US20180044329, US20180044305, US20180044304, US20180044303, US20180044350, US20180057455, US2018005748. 6. US20180045142, WO20180044963, WO2018044783, WO2018009505, WO20180044329, WO2 017066227, WO2017087777, US20170145025, WO2017079669, WO2017070089, US20171072 16. WO2017222976, US20170262253, WO2017205464, US20170320875, WO2017192961, WO2 017112730, US20170174679, WO2017106634, WO2017202744, WO2017202275, WO20172022 73, WO2017202274, WO2017202276, WO2017180769, WO2017118762, WO2016041511, WO2016039749, WO2016142835, WO2016142852, WO2016142886, WO2016142894 and WO2016142833.

[0243] In some embodiments, the other therapeutic agent is recombinant thymosin α-1. Examples of recombinant thymosin α-1 include NL-004 and pegylated thymosin α-1.

[0244] In some embodiments, the other therapeutic agents are Bruton's tyrosine kinase (BTK) inhibitors. Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and disclosed in US20140330015 (Ono Compounds listed in Pharmaceutical, US20130079327 (Ono Pharmaceutical) and US20130217880 (Ono Pharmaceutical).

[0245] In some embodiments, the other therapeutic agents are KDM inhibitors. In some embodiments, the KDM inhibitor is a KDM5 inhibitor. Examples of KDM5 inhibitors include compounds disclosed in WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation Pharmaceuticals), US20140371195 (Epitherapeutics), US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), and WO2014164708 (Quanticel). In some embodiments, the KDM inhibitor is a KDM1 inhibitor. Examples of KDM1 inhibitors include compounds disclosed in US9186337B2 (Oryzon Genomics) and GSK-2879552, RG-6016, or Y-2001.

[0246] In some embodiments, the other therapeutic agents are hepatitis B virus replication inhibitors. Examples of hepatitis B virus replication inhibitors include isotiafludine, IQP-HBV, RM-5038, and singantie.

[0247] In some embodiments, the other therapeutic agent is an arginase inhibitor. Examples of arginase inhibitors include CB-1158, C-201, and remixstat.

[0248] In some embodiments, the combination therapies described herein include gene therapy and / or cell therapy. Gene therapy and cell therapy include: gene modification to silence genes; gene-mediated methods of directly killing infected cells; designing the infusion of immune cells to replace most of the subject's own immune system to enhance the immune response to infected cells, or activating the patient's own immune system to kill infected cells, or seeking out and killing infected cells; and modifying cell activity to further alter gene-mediated endogenous immune reactivity to infection.

[0249] In some embodiments, the combination therapies described herein include gene editing agents. Gene editing systems may be selected from the group consisting of: CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing nuclease systems, and large-scale nuclease systems; for example, by targeted cleavage of cccDNA and alteration of one or more hepatitis B virus (HBV) viral genes. Altering (e.g., knocking out and / or knocking down) PreC, C, X, PreSI, PreS2, S, P, or SP genes means (1) reducing or eliminating the expression of PreC, C, X, PreSI, PreS2, S, P, or SP genes; (2) interfering with the function of precore, core, X protein, long surface protein, intermediate surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein, and / or hepatitis B splicing protein (HBe, HBc, HBx, PreS1, PreS2, S, Pol, and / or HBSP); or (3) reducing or eliminating the intracellular, serum, and / or parenchymal content of HBe, HBc, HBx, LHBs, MHBs, SHBs, Pol, and / or HBSP proteins. By targeting genes within HBV cccDNA and / or integrated into HBV DNA, one or more of the PreC, C, X, PreSI, PreS2, S, P and / or SP genes can be knocked down.

[0250] In some embodiments, the combination therapies described herein include CAR-T cell therapy. CAR-T cell therapy may comprise a population of immune effector cells modified to express a chimeric antigen receptor (CAR), wherein the CAR includes an HBV antigen-binding domain. The immune effector cell line is either T cells or NK cells. In some embodiments, the T cell line is CD4+ T cells, CD8+ T cells, or a combination thereof. The cells may be autologous or allogeneic.

[0251] In some embodiments, the combination therapies described herein include TCR-T cell therapy. TCR-T cell therapy may include T cells expressing HBV-specific T cell receptors. TCR-T cells may be engineered to target HBV-derived peptides presented on the surface of virus-infected cells. T cells expressing HBV surface antigen (HBsAg)-specific TCRs may be used. TCR-T therapies intended to treat HBV, such as LTCR-H2-1, may also be employed.

[0252] In some embodiments, methods of treating and / or preventing HBV infection include administering a combination therapy comprising the provided composition and one, two, three, or four other therapeutic agents selected from the group consisting of: adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®).

[0253] In some embodiments, a method of treating and / or preventing HBV infection includes administering a combination therapy comprising the provided composition and a first other therapeutic agent selected from the group consisting of: adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®).

[0254] In some embodiments, methods of treating and / or preventing HBV infection include administering a combination therapy comprising the provided composition and an HBV DNA polymerase inhibitor. In some embodiments, methods of treating and / or preventing HBV infection include administration of a combination therapy comprising the provided composition, an HBV DNA polymerase inhibitor, and at least one other therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, interferon α receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, compounds targeting HBcAg, cyclophilin inhibitors, HBV vaccines, HBV virus entry inhibitors, NTCP inhibitors, antisense oligonucleotides targeting viral mRNA, siRNA, miRNA gene therapy agents, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis B virus E antigen inhibitors, recombinant SRA protein, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, sshRNA, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus), bispecific antibodies, and "antibody-like" therapeutic proteins (e.g., DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs). ®, Fab derivatives or TCR-like antibodies), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators (HBV core or capsid protein modulators), retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, NOD2 stimulators, NOD1 stimulators, arginase inhibitors, STING agonists, PI3K inhibitors, lymphotoxin β-receptor activators, natural killer cell receptor 2B4 inhibitors, lymphocyte activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, CD137 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T lymphocyte attenuation protein inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon λ, recombinant thymosin α-1, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRPα modulators, ICOS modulators, CD27 modulators, CD70 modulators, OX40 modulators, postgenetic modifiers, NKG2D modulators, Tim-4 modulators, B7-H4 modulators, B7-H3 modulators, NKG2A modulators, GITR modulators, CD160 modulators, HEVEM modulators, CD161 modulators, Axl modulators, Mer modulators, Tyro modulators, gene modifiers or editing agents (e.g., CRISPR, including CRISPR-120). Cas9), zinc finger nucleases or synthetic nucleases (TALEN), IAP inhibitors, SMAC mimics, KDM5 inhibitors, IDO inhibitors, and hepatitis B virus replication inhibitors..

[0255] In some embodiments, methods of treating and / or preventing HBV infection include administering a combination therapy comprising (i) the provided composition; (ii) an HBV DNA polymerase inhibitor; and (iii) one or more of the following: an immunomodulator, a TLR modulator, an HBsAg inhibitor, an HBsAg secretion or assembly inhibitor, an HBV therapeutic vaccine, an HBV antibody (including an HBV antibody targeting the surface antigen of hepatitis B virus), a bispecific antibody, and an "antibody-like" therapeutic protein (e.g., DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs). Other therapeutic agents comprising the group consisting of ®, Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators, and one or two other therapeutic agents selected from the group consisting of HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core or capsid protein modulators).

[0256] In some embodiments, methods of treating and / or preventing HBV infection include administering a combination therapy comprising the provided composition, an HBV DNA polymerase inhibitor, and a second other therapeutic agent selected from at least the following groups: immunomodulators, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus) and bispecific antibodies and "antibody-like" therapeutic proteins (e.g., DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilic inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, argininase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators.

[0257] In some embodiments, methods of treating and / or preventing HBV infection include administering a combination therapy comprising the provided composition, an HBV DNA polymerase inhibitor, and a second other therapeutic agent selected from at least the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein inhibitors).

[0258] In some embodiments, a method of treating and / or preventing HBV infection includes administering a combination therapy comprising (i) the provided composition; and (ii) a first other therapeutic agent selected from the group consisting of: adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®).And at least a second other therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, compounds targeting HBcAg, cyclophilin inhibitors, HBV vaccines, HBV virus entry inhibitors, NTCP inhibitors, antisense oligonucleotides targeting viral mRNA, siRNA, miRNA gene therapy agents, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis B virus e antigen inhibitors, recombinant SRA protein, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, sshRNA, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus) and bispecific antibodies and "antibody-like" therapeutic proteins (e.g., DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs). ®, Fab derivatives and TCR-like antibodies), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators (HBV core or capsid protein modulators), retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, NOD2 stimulators, NOD1 stimulators, IDO inhibitors, recombinant thymosin α-1, arginase inhibitors, STING agonists, PI3K inhibitors, lymphotoxin β-receptor activators, natural killer cell receptor 2B4 inhibitors, lymphocyte activation gene 3 inhibitors, CD160 inhibitors, ipi4 inhibitors, CD137 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T lymphocyte inhibitors Inhibitors of globular attenuation proteins, postgenetic modifiers, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon λ, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRPα modulators, ICOS modulators, CD27 modulators, CD70 modulators, OX40 modulators, NKG2D modulators, Tim-4 modulators, B7-H4 modulators, B7-H3 modulators, NKG2A modulators, GITR modulators, CD160 modulators, HEVEM modulators, CD161 modulators, Axl modulators, Mer modulators, Tyro modulators, gene modifiers or editing agents (e.g., CRISPR, including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), IAP inhibitors, SMAC mimics, KDM5 inhibitors, and hepatitis B virus replication inhibitors.

[0259] In some embodiments, a method of treating and / or preventing HBV infection includes administering a combination therapy comprising (i) the provided composition; and (ii) a first other therapeutic agent selected from the group consisting of: adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®).(iii) at least a second other therapeutic agent selected from the group consisting of: pegylated interferon α-2b (PEG-INTRON®), MULTIFERON®, interferon α-1b (HAPGEN®), interferon α-2b (INTRON A®), pegylated interferon α-2a (PEGASYS®), interferon α-n1 (HUMOFERON®), ribavirin, interferon β-1a (AVONEX®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, oligoglycosides, Zutectra, Shaferon, interferon α-2b (AXXO), Alfaferone, interferon α-2b (BioGeneric Pharma), Feron, interferon-α2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, Interferon α-2b (IFN, Laboratorios Bioprofarma), Interferon α-2b, Kalferon, Pegnano, Feronsure, PegiHep, Interferon α-2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, Interferon α-2b (Amega), Interferon α-2b (Virchow), Pegylated Interferon α-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, Interferon α-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, MOR-22, Interleukin-2 (IL-2, Immunex), Recombinant Human Interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, alophiron, and simvaplein.

[0260] In some embodiments, a method of treating and / or preventing HBV infection includes administering a combination therapy comprising (i) the provided composition; and (ii) a first other therapeutic agent selected from the group consisting of: adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV). (iii) at least a second other therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus) and bispecific antibodies and "antibody-like" therapeutic proteins (e.g., DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives or TCR-like antibodies), cyclophilic inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, arginase inhibitors, PI3K inhibitors, PD-1 inhibitors, PD-L1 inhibitors, IDO inhibitors and NOD2 stimulators.

[0261] In some embodiments, a method of treating and / or preventing HBV infection includes administering a combination therapy comprising (i) the provided composition; and (ii) a first other therapeutic agent selected from the group consisting of: adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV). (iii) at least a second other therapeutic agent selected from the group consisting of: HBV entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein modulators).

[0262] In some embodiments, a method of treating and / or preventing HBV infection includes administering a combination therapy comprising (i) the composition provided; (ii) a first other therapeutic agent selected from the group consisting of: adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); and (iii) one, two, or three other therapeutic agents selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus), bispecific antibodies, and "antibody-like" therapeutic proteins (e.g., DARTs). (iv) HBV virus entry inhibitors, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives or TCR-like antibodies, cyclophilin inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators; and (iv) one or two other therapeutic agents selected from the group consisting of: HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core or capsid protein modulators).

[0263] In some embodiments, a method of treating and / or preventing HBV infection includes administering a combination therapy comprising (i) the composition provided; (ii) a first other therapeutic agent selected from the group consisting of: adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); and (iii) one or two other therapeutic agents selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus), and bispecific antibodies and "antibody-like" therapeutic proteins (e.g., DARTs). (iv) HBV virus entry inhibitors, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives or TCR-like antibodies, cyclophilin inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators; and (iv) one or two other therapeutic agents selected from the group consisting of: HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core or capsid protein modulators).

[0264] In some embodiments, a method of treating and / or preventing HBV infection includes administering a combination therapy comprising (i) the provided composition; and (ii) a first other therapeutic agent selected from the group consisting of: adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV). (iii) one, two, three, or four other therapeutic agents selected from the group consisting of: immunomodulators, TLR7 modulators, TLR8 modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies targeting the surface antigen of hepatitis B virus) and bispecific antibodies and "antibody-like" therapeutic proteins (e.g., DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilin inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, NOD2 stimulators, HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, siRNA, miRNA gene therapy agents, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein modulators).

[0265] In some embodiments, methods of treating and / or preventing HBV infection include administering a combination therapy comprising the provided composition and compounds such as those disclosed in the following documents: U.S. Patent Publication No. 2010 / 0143301 (Gilead Sciences), U.S. Patent Publication No. 2011 / 0098248 (Gilead Sciences), U.S. Patent Publication No. 2009 / 0047249 (Gilead Sciences), U.S. Patent No. 8722054 (Gilead Sciences), U.S. Patent Publication No. 2014 / 0045849 (Janssen), U.S. Patent Publication No. 2014 / 0073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US Public Case No. 2014 / 0350031 (Janssen), WO2014 / 023813 (Janssen), US Public Case No. 2008 / 0234251 (Array Biopharma), US Public Case No. 2008 / 0306050 (Array Biopharma), US Public Case No. 2010 / 0029585 (Ventirx Pharma), US Public Case No. 2011 / 0092485 (Ventirx Pharma), US2011 / 0118235 (Ventirx Pharma), US Public Case No. 2012 / 0082658 (Ventirx Pharma), US Public Case No. 2012 / 0219615 (Ventirx Pharma), US Public Case No. 2014 / 0066432 (Ventirx Pharma) Pharma), U.S. Publication No. 2014 / 0088085 (Ventirx Pharma), U.S. Publication No. 2014 / 0275167 (Novira Therapeutics), U.S. Publication No. 2013 / 0251673 (Novira Therapeutics), U.S. Patent No. 8513184 (Gilead Sciences), U.S. Publication No. 2014 / 0030221 (Gilead Sciences), U.S. Publication No. 2013 / 0344030 (Gilead Sciences), U.S. Publication No. 2013 / 0344029 (Gilead Sciences), US20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), U.S. Publication No. 2014 / 0343032 (Roche), WO2014037480 (Roche), U.S. Publication No. 2013 / 0267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015 / 059212 (Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652 (Novira), US20150259324, (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche), US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (Flexus Biosciences, Inc.), WO2015188085 (Flexus Biosciences, Inc., US Publication No. 2014 / 0330015 (Ono Pharmaceutical), US Publication No. 2013 / 0079327 (Ono Pharmaceutical), US Publication No. 2013 / 0217880 (Ono Pharmaceutical), WO2016057924 (Genentech / Constellation Pharmaceuticals), US20140275092 (Genentech / Constellation Pharmaceuticals), US20140371195 (Epitherapeutics), and US20140371214(Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel), US9186337B2 (Oryzon Genomics); and other drugs used to treat HBV; and combinations thereof.

[0266] In some embodiments, the provided composition can be combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents at any dosage amount.

[0267] In some embodiments, the provided composition is combined with tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the provided composition is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the provided composition is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the provided composition is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the provided composition is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. The provided composition may be combined with any dosage of the pharmaceutical agents provided herein, as each dosage combination is specifically and individually listed.

[0268] In some embodiments, the provided composition is combined with 100-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, or tenofovir disoproxil fumarate. In some embodiments, the provided composition is combined with 100 mg to 150 mg, 100 mg to 200 mg, 100 mg to 250 mg, 100 mg to 300 mg, 100 mg to 350 mg, 150 mg to 200 mg, 150 mg to 250 mg, 150 mg to 300 mg, 150 mg to 350 mg, 150 mg to 400 mg, 200 mg to 250 mg, 200 mg to 300 mg, 200 mg to 350 mg, 200 mg to 400 mg, 250 mg to 350 mg, 250 mg to 400 mg, 350 mg to 400 mg, or 300 mg to 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, or tenofovir disoproxil fumarate. In some embodiments, the provided composition is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemispheric acid, or tenofovir disoproxil fumarate. In some embodiments, the provided composition is combined with 250 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemispheric acid, or tenofovir disoproxil fumarate. In some embodiments, the provided composition is combined with 150 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemispheric acid, or tenofovir disoproxil fumarate. The provided composition may be combined with any dosage amount of the provided composition with the pharmaceutical agents provided herein, as each dosage combination is specifically and individually listed.

[0269] In some embodiments, a kit is provided comprising a combination of the compositions disclosed herein with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents. The provided compositions may be used in the kit, as each and every composition is specifically and individually listed for use in the kit. HIV combination therapy

[0270] In some embodiments, a method is provided for treating HIV infection in humans who are infected or at risk of such infection, comprising administering to a human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four other therapeutic agents in a therapeutically effective amount. In one embodiment, a method is provided for treating HIV infection in humans who are infected or at risk of such infection, comprising administering to a human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four other therapeutic agents in a therapeutically effective amount.

[0271] In some embodiments, a method of treating HIV infection is provided, comprising administering to a human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a combination of one, two, three, or four other therapeutic agents in a therapeutically effective amount.

[0272] In one embodiment, a pharmaceutical composition is provided comprising a combination of the compound disclosed herein or a pharmaceutically acceptable salt thereof with one, two, three or four other therapeutic agents and pharmaceutically acceptable carriers, diluents or excipients.

[0273] In some embodiments, the present invention provides a method for treating HIV infection comprising administering to a patient in need a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a combination of one, two, three, or four other therapeutic agents suitable for treating HIV infection in a therapeutically effective amount.

[0274] In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more other therapeutic agents. In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two other therapeutic agents. In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, or four other therapeutic agents. In other embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with three other therapeutic agents. In other embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with four other therapeutic agents. The one, two, three, four, or more other therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or may be selected from different classes of therapeutic agents. HIV combination therapy administration

[0275] In some embodiments, one, two, three, or four other therapeutic agents of the compound disclosed herein are administered together. Co-administration of the compound disclosed herein with one, two, three, or four other therapeutic agents generally refers to the simultaneous or sequential administration of the compound disclosed herein and one, two, three, or four other therapeutic agents, such that a therapeutically effective amount of the compound disclosed herein and one, two, three, or four other therapeutic agents are present in the patient's body. When administered sequentially, the combination may be administered two or more times.

[0276] Co-doping includes administering a unit dose of the compound disclosed herein before or after administering a unit dose of one, two, three, or four other therapeutic agents. For example, the compound disclosed herein may be administered within seconds, minutes, or hours after administering one, two, three, or four other therapeutic agents. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one, two, three, or four other therapeutic agents within seconds or minutes. Alternatively, a unit dose of one, two, three, or four other therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within seconds or minutes. In other embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one, two, three, or four other therapeutic agents after a period of several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one, two, three, or four other therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein after a period of several hours (e.g., 1-12 hours).

[0277] In some embodiments, the compounds disclosed herein are combined with one, two, three or four other therapeutic agents in a single dosage form for simultaneous administration to a patient, such as in a solid dosage form for oral administration.

[0278] In some embodiments, a kit is provided comprising a combination of the compounds disclosed herein or their pharmaceutically acceptable salts with one or more (e.g., one, two, three, or four) other therapeutic agents.

[0279] In some embodiments, compounds of any formula disclosed herein are formulated into tablets, which may, where appropriate, contain one or more other compounds that can be used to treat HIV. In some embodiments, the tablets may contain another active ingredient for treating HIV, such as an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosite) integrase inhibitor, a pharmacokinetic enhancer, or a combination thereof.

[0280] In one specific embodiment, the kit includes the compounds disclosed herein or their pharmaceutically acceptable salts, HIV nucleoside or nucleotide reverse transcriptase inhibitors, and HIV capsid inhibitors or HIV capsid polymerization inhibitors.

[0281] In some embodiments, these tablets are suitable for once-daily administration. HIV combination therapy

[0282] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HIV combination therapy. In the above embodiments, one or more other therapeutic agents may be anti-HIV agents. In the above embodiments, one or more other therapeutic agents or pharmaceuticals may be anti-HIV agents selected from the following: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosite) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (e.g., CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (e.g., chimeric antigen receptor T cells (CAR-T) and modified T cell receptors (TCR-T), autologous T cell therapy), latency reversal agents, compounds targeting the HIV capsid, capsid polymerization inhibitors, HIV bNAb, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infection factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, protein 1 modulators containing COMM domains, HIV ribonuclease H inhibitors, resveratrol modulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines and combinations thereof.In some embodiments, other therapeutic agents may be selected from HIV capsid inhibitors, HIV Tat or Rev inhibitors, modified B cells, fatty acid synthase inhibitors, HIV-1 Nef modulators, TNF α ligand inhibitors, HIV Nef inhibitors, IFN antagonists, CD3 antagonists, CDK-4 inhibitors, CDK-6 inhibitors, cytochrome P450 3 inhibitors, CXCR4 modulators, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein modulators, RNA polymerase modulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, and combinations thereof.

[0283] In some embodiments, other therapeutic agents are selected from the group consisting of: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allolytic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins and combinations thereof.

[0284] In some embodiments, other therapeutic agents or pharmaceuticals are selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latency reversal agents, HIV bNAb, TLR7, TLR8 and TLR9 agonists, HIV vaccines, intercytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies that recruit T cells and NK cells, chimeric T cell receptors that target HIV antigens, pharmacokinetic enhancers, and other pharmaceuticals for the treatment of HIV, as well as combinations thereof.

[0285] In some embodiments, one or more other therapeutic agents are selected from derognetovir, carboplatinavir, islatravir, darunavir, biclotinavir, afavirine, rilpivirine, and lenacapavir, and combinations thereof.

[0286] In some embodiments, one or more other therapeutic agents are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosite) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immunotherapy-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof. HIV combination therapy

[0287] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HIV combination drug. Examples of combination therapies include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (etigamivir, clobistable, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, clobistable, and etigamivir); SYMTUZA® (darunavir, tenofovir alafenamide, emtricitabine, and clobistable); BIKTARVY® (Bicitrahiver, tenofovir alafenamide, and emtricitabine); Bicitrahiver, tenofovir disoproxil fumarate, and emtricitabine; Bicitrahiver, tenofovir alafenamide, and lamivudine; Bicitrahiver, tenofovir disoproxil fumarate, and lamivudine; Bicitrahiver, abacavir, and lamivudine; Efaviram, lamivudine, and tenofovir disoproxil fumarate; Lamivudine and tenofovir disoproxil fumarate; Tenofovir and lamivudine; Tenofovir alafenamide and emtricitabine; Tenofovir alafenamide hemifumarate and emtricitabine; Tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; Tenofovir alafenamide hemifumarate, emtricitabine, cobistat, and ertigvir; COMBIVIR ® (Zidovudine and Lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; Abacavir Sulfate and Lamivudine; ABC+3TC); KALETRA® (ALUVIA®; Lopinavir and Ritonavir); TRIUMEQ® (Drogvir, Abacavir and Lamivudine); JULUCA® (Drogvir, Ripilvirine); TRIZIVIR® (Abacavir Sulfate, Zidovudine and Lamivudine; ABC+AZT+3TC); Drogvir and Lamivudine; Drogvir and Abacavir; Carboticlavix and Lamivudine; Carboticlavix and Abacavir; Carboticlavix and Ripilvirine; Atazanavir and Cobicista; Atazanavir Sulfate and Cobicista; Atazanavir Sulfate and Ritonavir; Darunavir and Cobicista; Drogvir and Ripilvirine Pivirine; Derogavir and Rilpivirine Hydrochloride; Derogavir, Abacavir Sulfate and Lamivudine; Lamivudine, Nevirapine and Zidovudine; Rettagvir and Lamivudine; Doraviline, Lamivudine and Tenofovir Disoproxil Fumarate; Doraviline, Lamivudine and Tenofovir Disoproxil Fumarate; Derogavir + Lamivudine; Lamivudine + Abacavir + Zidovudine; Lamivudine + Abacavir;Lamivudine + tenofovir disoproxil fumarate; lamivudine + zidovudine + nevirapine; lopinavir + ritonavir; lopinavir + ritonavir + abacavir + lamivudine; lopinavir + ritonavir + zidovudine + lamivudine; tenofovir + lamivudine; and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride. In some embodiments, other agents are tenofovir analogs, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, lamivudine, carboplatinavir + rilpivirine, 3-BNC117 + ibavitritide, elpida (elfavirine, VM-1500) and VM-1500A or combinations thereof. Other HIV medications

[0288] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one other HIV drug. Examples of other medications used to treat HIV include acemenopause, aripiprvir, banana lectin, deferiprone, gamimoline, metronidazole, natrozine, prostatin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, and PA-1050040. (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Imgro, and VIR-576. Other examples of other drugs used to treat HIV include (but are not limited to) AAV-eCD4-Ig gene therapy, bevirimat derivatives, ABBV-382, APH0202, bryozoin-1, bryozoin analogs, BG-HIV, BRII-732, CS-TATI-1, antisense oligonucleotides modified with fluoro-β-D-arabinose (FANA), FX-101, griffithsin, GSK-3739937, GSK-3739937. (Long-acting), Hydroxychloroquine, IMB-10035, JL-18008, LADAVRU, MK-8558, OB-002H, ODE-Bn-TFV, PC-707, QF-036, S-648414, DIACC-1010, Fasnall, 2-CLIPS peptide, HRF-4467, Thrombin-sensitive protein analog, TBL-1004HI, VG-1177, xl-081, AVI-CO-004, rfhS P-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, IML-106, antiviral fc conjugate (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, HiviCide-I, T-1144 and combinations thereof. HIV protease inhibitors

[0289] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HIV protease inhibitor. Examples of HIV protease inhibitors include ampravir, atazanavir, becanavir, darunavir, furazanavir, furazanavir calcium, indinavir, indinavir sulfate, lopinavir, nifenavir, nifenavir mesylate, ritonavir, saquinavir, saquinavir mesylate, telanavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, and TMC-310911. Other examples of HIV protease inhibitors include (but are not limited to) ASC-09 + ritonavir, AEBL-2, GS-1156, GRL-02031, and combinations thereof.

[0290] Other examples of HIV protease inhibitors are set forth in, for example, U.S. Patent No. 10,294,234 and U.S. Patent Application Publication Nos. US2020030327 and US2019210978. HIV reverse transcriptase inhibitors

[0291] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HIV reverse transcriptase inhibitor. Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapirine, deraviridine, deraviridine mesylate, doravirine, efavirenz, ectrevirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and elfavirine (VM-1500). Other examples of HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors include (but are not limited to) ACC-008, AIC-292, F-18, KM-023, PC-1005, M1-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, favirine (continuously released oral formulation for HIV infection), doravirine + isravir (fixed-dose combination / oral tablet formulation for HIV-1 infection), favirine (long-acting injectable nano suspension for HIV infection), or combinations thereof.

[0292] Examples of HIV nucleoside or nucleotide reverse transcriptase inhibitors include adefovir, adefovir dipivoxil, arudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, VIDEX®, and VIDEX EC. ® (desoxyinosine, DDL), abacavir, abacavir sulfate, alovudine, aritabine, sensav, desoxyinosine, evitabine, fetinavirvir, fosifidoxime, CMX-157, dapoxetine, doravirin, ectavirine, OCR-5753, tenofovir disoproxil fumarate, fozivudine, lamivudine, phosphatidylcholine, stavudine, zalcitabine, zidovudine, rovafovir-etarafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, and KP-1461. Other examples of HIV nucleoside or nucleotide reverse transcriptase inhibitors include (but are not limited to) tenofovir octadecyloxyethyl ester (AGX-1009), MK-8583, and combinations thereof.

[0293] Other examples of HIV nucleoside or nucleotide reverse transcriptase inhibitors include (but are not limited to) those described in patent publications US2007049754, US2016250215, US2016237062, US2016251347, US2002119443, US2013065856, US2013090473, US2014221356 and WO04096286. HIV integrase inhibitors

[0294] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HIV integrase inhibitor. Examples of HIV integrase inhibitors include erticagvir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, ginsenoside tricarboxylic acid, ginsenoside tricarboxylic acid derivatives, phenethyl caffeate, phenethyl caffeate derivatives, tyrosine phosphorylation inhibitors, tyrosine phosphorylation inhibitor derivatives, quercetin, quercetin derivatives, retigvir, derogvir, JTK-351, bicretivavir, and AVX. -15567, diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, lederma, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, and carboplatinavir.

[0295] Examples of HIV noncatalytic site or allolytic integrase inhibitors (NCINIs) include CX-05045, CX-05168, and CX-14442. Other examples of HIV integrase inhibitors include (but are not limited to) erticagvir (extended-release microcapsules), pegylated retegvir, carboplatinavir (long-acting injectable), STP-0404, or combinations thereof.

[0296] Other examples of HIV capsid inhibitors include (but are not limited to) those described in U.S. Patent Application Publication Nos. US2014221356 and US2016016973. HIV infection factor inhibitors

[0297] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HIV infection factor inhibitor. Examples of HIV infection factor inhibitors include (but are not limited to) 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzylamine derivatives. HIV entry inhibitors

[0298] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HIV entry (fusion) inhibitor. Examples of HIV entry (fusion) inhibitors include cefoperazone, CCR5 inhibitors, gp41 inhibitors, CD4 linker inhibitors, gp120 inhibitors, and CXCR4 inhibitors. Other examples of HIV entry (fusion) inhibitors include (but are not limited to) AAR-501, LBT-5001, gp160 inhibitors, and combinations thereof.

[0299] Examples of CCR5 inhibitors include apravirone, velivorone, maravirone, cikvirone, leuromab (PRO-140), adatabive (RAP-101), nifevirone (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, peptide C25P, TD-0680, and vMIP (Haimipu). Other examples of CCR5 inhibitors include (but are not limited to) maravirone (long-acting injectable nanoemulsion), thioraviroc, and combinations thereof.

[0300] Examples of gp41 inhibitors include epovitide, enfuvirtide, BMS-986197, enfuvirtide biomodifiers, enfuvirtide biosimilars, HIV fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifvirtide. Examples of gp41 inhibitors include (but are not limited to) grefterone (a gp41 / gp120 / gp160 inhibitor), CPT-31, Cl3hmAb, lipuvirtide, HIV-1 fusion inhibitors (P26-Bapc), and combinations thereof.

[0301] Examples of CD4 linker inhibitors include ibalizumab and CADA analogues.

[0302] Examples of gp120 inhibitors include Radha-108 (Lexitriol) 3B3-PE38, banana lectin, bentonite-based nanoparticles, Fostersave-Ambutanol, IQP-0831, and BMS-663068. Other examples of gp120 inhibitors include (but are not limited to) anti-HIV antimicrobial agents, BMS818251, VVX-004, and combinations thereof.

[0303] Examples of gp160 inhibitors include (but are not limited to) fangchinoline.

[0304] Examples of CXCR4 inhibitors include praxavir, ALT-1188, N15 peptide, and vMIP (hemipl). HIV maturation inhibitors

[0305] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HIV maturation inhibitor. Examples of HIV maturation inhibitors include BMS-955176, GSK-3640254, and GSK-2838232. Latent reversal agent

[0306] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one latency reversal agent. Examples of latency reversal agents include histoprotein deacetylase (HDAC) inhibitors, proteasome inhibitors (e.g., Vilcard), protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid or suberoyl, anilide, and hydroxamic acid), IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors (e.g., lagozolaridine analogs, APH-0812, GSK-343) and steroid receptor modulators. Other examples of latency reversal agents include (but are not limited to) TLR receptor (TLR) agonists (including TLR7 agonists (e.g., GS-9620), TLR8 agonists, and TLR9 agonists), (e.g., ZL-0580, apatalone), IAP antagonists (inhibitors of apoptosis proteins, such as APG-1387, LBW-242), SMAC mimics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio-1143), NIZ-985, IL-15 modulating antibodies (including IL-15, IL-15 fusion proteins, and IL-15 receptor agonists) and combinations thereof.

[0307] Examples of HDAC inhibitors include romidesin, voridoxetine, and pabisostat.

[0308] Examples of PKC activators include indolinamide, prostatin, phorbol B, and DAG-lactone.

[0309] Other examples of TLR7 agonists include (but are not limited to) those described in U.S. Patent Application Publication No. US2010143301.

[0310] Other examples of TLR8 agonists include (but are not limited to) those described in U.S. Patent Application Publication No. US2017071944. HDAC inhibitors

[0311] In some embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are combined with inhibitors of histoprotein deacetases (e.g., histoprotein deacetase 1, histoprotein deacetase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene number: 9734)). Examples of HDAC inhibitors include (but are not limited to) abexistat, ACY-241, AR-42, BEBT-908, belinstat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fepistat), entecavir, gilvesta, mosetinostazol, pabistazol, propistazol, quincilalstat (JNJ-26481585), remixstat, relinstat, romidesin, SHP-141, TMB-ADC, valproic acid (VAL-001), voridstat, tenostine, remixstat, and entecavir. Capsid inhibitors

[0312] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one capsid inhibitor. Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-destructive compounds, HIV nucleocapsid p7 (NCp7) inhibitors (e.g., azodimethylamine, HIV p24 capsid protein inhibitors, GS-6207, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series). In some embodiments, at least one compound disclosed herein is combined with GS-6207. Other examples of capsid inhibitors include (but are not limited to) linakapavir, GS-CA1, PF-3450074, HIV-1 capsid inhibitors (HIV-1 infection, Shandong University), compounds and combinations thereof described in GSK Patent Publication WO2019 / 087016.

[0313] Other examples of capsid inhibitors include (but are not limited to) those described in U.S. Patent Application Publication Nos. US2018051005 and US2016108030. Cytochrome P450 3 inhibitors

[0314] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one cytochrome P450 3 inhibitor. Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in U.S. Patent No. 7,939,553. RNA polymerase regulators

[0315] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one RNA polymerase regulator. Examples of RNA polymerase regulators include (but are not limited to) those described in U.S. Patent Nos. 10,065,958 and 8,008,264. Immune checkpoint modulators

[0316] In various embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are combined with one or more inhibitors or blockers of inhibitory immune checkpoint proteins or receptors and / or one or more stimulators, activators, or agonists of stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune escape by infected cells. Activating or stimulating stimulating immune checkpoints can increase the efficacy of immune checkpoint inhibitors in the treatment of infections. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (as reviewed in Xu et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate NK cell responses (as reviewed in Davis et al., Semin Immunol. (2017) 31:64-75 and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0317] Examples of immune checkpoint proteins or receptors include (but are not limited to) CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2); protein 2 containing transmembrane and immunoglobulin domains (TMIGD2, CD28H); CD84 (LY9B, SLAMF5); CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); T cell activation inhibitory factor 1 containing V-set domains (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-related protein 2. (HHLA2, B7H7); T cell costimulatory factors (ICOS, CD278); T cell costimulatory ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated protein (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); Programmed cell death protein 1 (PDCD1, PD1, PD-1); Cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; NECTIN2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); Proteins containing PVR-associated immunoglobulin domains (PVRIG, CD112R); T-cell immune receptor with Ig and ITIM domains (TIGIT); Protein 4 containing T-cell immunoglobulin and mucin domains (TIMD4;TIM4); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); Galactoglobulin 9 (LGALS9); Lymphocyte activating protein 3 (LAG3, CD223); Signal transduction lymphocyte activating molecule family member 1 (SLAMF1, SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); Early retinoic acid transcript 1E (RAET1E; ULBP4); Early retinoic acid transcript 1G (RAET1G; ULBP5); Early retinoic acid transcript 1L (RAET1L; ULBP6); Lymphocyte activating protein 3 (CD223); killer cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail (KIR, CD158E1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptors with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin-like receptors with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); and SLAM family member 7 (SLAMF7).

[0318] In various embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with one or more blockers or inhibitors of one or more T-cell suppressive immune checkpoint proteins or receptors. Elucidating T-cell suppressive immune checkpoint proteins or receptors include (but are not limited to) CD274 (CD274, PDL1, PD-L1); programmed cell death protein 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death protein 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); T-cell activation inhibitory factor 1 containing a V-set domain (VTCN1, B7H4); V-se immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated proteins (BTLA)); proteins containing PVR-associated immunoglobulin domains (PVRIG, CD112R); T cell immune receptors with Ig and ITIM domains (TIGIT); lymphocyte activation protein 3 (LAG3, CD223); hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); galactolectin 9 (LGALS9); killer cell immunoglobulin-like receptors (KIR, CD158E1) having three Ig domains and a long cytoplasmic tail 1; killer cell immunoglobulin-like receptors (KIR2DL1) having two Ig domains and a long cytoplasmic tail 1; killer cell immunoglobulin-like receptors (KIR2DL2) having two Ig domains and a long cytoplasmic tail 2; killer cell immunoglobulin-like receptors (KIR2DL3) having two Ig domains and a long cytoplasmic tail 3; and killer cell immunoglobulin-like receptors (KIR3DL1) having three Ig domains and a long cytoplasmic tail 1. In various embodiments, the agents as described herein are combined with one or more agonists or activators of one or more T cell-stimulating immune checkpoint proteins or receptors.Elucidating T-cell stimulating immune checkpoint proteins or receptors include (but are not limited to) CD27, CD70; CD40, CD40LG; inducible T-cell costimulatory factors (ICOS, CD278); inducible T-cell costimulatory factor ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; conjugative cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[0319] In various embodiments, the compound as described herein or a pharmaceutically acceptable salt thereof is combined with one or more of the blocking agents or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Elucidated NK cell inhibitory immune checkpoint proteins or receptors include (but are not limited to) killer cell immunoglobulin-like receptors (KIR, CD158E1) having three Ig domains and a long cytoplasmic tail 1; killer cell immunoglobulin-like receptors (KIR2DL1) having two Ig domains and a long cytoplasmic tail 1; killer cell immunoglobulin-like receptors (KIR2DL2) having two Ig domains and a long cytoplasmic tail 2; killer cell immunoglobulin-like receptors (KIR2DL3) having two Ig domains and a long cytoplasmic tail 3; killer cell immunoglobulin-like receptors (KIR3DL1) having three Ig domains and a long cytoplasmic tail 1; killer cell lectin-like receptors C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptors D1 (KLRD1, CD94). In various embodiments, the agents as described herein are combined with one or more agonists or activators of one or more NK cell stimulating immune checkpoint proteins or receptors. Elucidating NK cell-stimulated immune checkpoint proteins or receptors include (but are not limited to) CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, Davis et al., Semin Immunol. (2017) 31:64-75; Fang et al., Semin Immunol. (2017) 31:37-54; and Chiossone et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0320] In some embodiments, one or more immune checkpoint inhibitors comprise protein-based (e.g., antibody or fragment thereof or antibody mimic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors comprise small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitors of CD274 or PDCD1 are selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002.

[0321] Examples of drugs that can be co-administered with a CTLA4 inhibitor include (but are not limited to) ipilimumab, trimemumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), and KN-046. (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4) and AK-104 (CTLA4 / PD-1).

[0322] Examples of drugs that can be co-administered with PD-L1 (CD274) or PD-1 (PDCD1) inhibitors include (but are not limited to) pembrolizumab, nivorumab, cimetuzumab, pilizumab, AMP-224, MEDI0680 (AMP-514), sparizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, and JS-001. (Toripalimab), JNJ-63723283, Genomeamarab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (Camrelizumab), Sym-021, ABBV-181 (Budigalimab), PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (Dostalimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308) Sintilimab, HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1) and INBRX-105 (4-1BB / PDL1).

[0323] In various embodiments, the agents as described herein are combined with anti-TIGIT antibodies (e.g., BMS-986207, RG-6058, and AGEN-1307). TNF receptor superfamily (TNFRSF) agonists or activators

[0324] In various embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are combined with agonists of one or more TNF receptor superfamily (TNFRSF) members, such as agonists of one or more of the following: TNFRSF1A (NCBI genotype: 7132), TNFRSF1B (NCBI genotype: 7133), TNFRSF4 (OX40, CD134; NCBI genotype: 7293), TNFRSF5 (CD40; NCBI genotype: 958), TNFRSF6 (FAS; NCBI genotype: 355), TNFRSF7 (CD27; NCBI genotype: 939), TNFRSF8 (CD30; NCBI genotype: 943), TNFRSF9 (4-1BB, CD137; NCBI genotype: 3604), TNFRSF10A (CD261, DR4, TRAILR1; NCBI genotype: 8797), TNFRSF10B (CD262, DR5, TRAILR2; NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3; NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4; NCBI gene ID: 8793), TNFRSF11A (CD265, RANK; NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266; NCBI gene ID: 51330), TNFRSF13B (CD267; NCBI gene ID: 23495), TNFRSF13C (CD268; NCBI gene ID: 115650), TNFRSF16 (NGFR, CD271; NCBI gene ID: 4804), TNFRSF17 (BCMA, CD269; NCBI gene ID: 608), TNFRSF18 (GITR, CD357; NCBI gene number: 8784), TNFRSF19 (NCBI gene number: 55504), TNFRSF21 (CD358, DR6; NCBI gene number: 27242) and TNFRSF25 (DR3; NCBI gene number: 8718).

[0325] Examples of antibodies that can be co-administered with anti-TNFRSF4 (OX40) include (but are not limited to) MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0326] Examples of antibodies that can be co-administered with anti-TNFRSF5 (CD40) include (but are not limited to) RG7876, SEA-CD40, APX-005M and ABBV-428.

[0327] In some embodiments, the anti-TNFRSF7 (CD27) antibody vallizumab (CDX-1127) is co-administered.

[0328] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include (but are not limited to) urirolumab, urirolumab (PF-05082566), AGEN2373 and ADG-106.

[0329] Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administered include (but are not limited to) MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, an antibody or fragment thereof that co-targets TNFRSF4 (OX40) and TNFRSF18 (GITR) may be co-administered. These antibodies are described, for example, in WO2017096179 and WO2018089628. Bi- and tri-specific natural killer (NK) cell adaptors

[0330] In various embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are combined with bispecific NK cell adaptors (BiKE) or trispecific NK cell adaptors (TriKE) (e.g., without Fc) or bispecific antibodies (e.g., with Fc) targeting: NK cell activation receptors (e.g., CD16A), C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), native cytotoxic receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (which mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Suitably, anti-CD16 binding bispecific molecules may or may not have Fc. Co-administered bispecific NK cell adjuvants targeting CD16 and one or more HIV-associated antigens as described herein. BiKE and TriKE are described, for example, in the following literature: Felices et al., Methods Mol Biol. (2016) 1441:333-346; Fang et al., Semin Immunol. (2017) 31:37-54. Examples of trispecific NK cell adjuvants (TRiKE) include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3 TriKe. Indoleamine-pyrrole-2,3-dioxanase (IDO1) inhibitors

[0331] In various embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are combined with inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene number: 3620). Examples of IDO1 inhibitors include (but are not limited to), BLV-0801, epalrestat, F-001287, GBV-1012, GBV-1028, GDC-0919, insimod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranoquinone derivatives (SN-35837), remixstat, SBLK-200802, BMS-986205, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916. Immunotherapy

[0332] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one immunotherapy. Examples of immunotherapy include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13 modulators; programmed cell death protein 1 (Pd-1) modulators; and programmed cell death ligand 1 (PD-1) modulators. (PDL-1) regulator; IL-15 regulator; DermaVir; interleukin-7; hydroxychloroquine sulfate tablets (hydroxychloroquine); purulin (aldextromethorphan, IL-2); interferon α; interferon α-2b; interferon α-n3; pegylated interferon α; interferon γ; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; polymeric polyethyleneimine (PEI); guapentin; rapamod; IL-12; WF- 10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, Norfelon, pegylated interferon α-2a, pegylated interferon α-2b, recombinant interleukin-15, RPI-MN, STING regulator, RIG-I regulator, NOD2 regulator, SB-9200 and IR-103.

[0333] Examples of TLR agonists include vesamimod (GS-9620), lefemod, tilopoxmod, rapamod, DSP-0509, AL-034, G-100, copitomod, AST-008, motomod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, and telatomomod. TLR receptor agonists

[0334] In various embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are combined with agonists of torticollis receptors (TLRs), such agonists being, for example, agonists of TLR1 (NCBI genotype: 7096), TLR2 (NCBI genotype: 7097), TLR3 (NCBI genotype: 7098), TLR4 (NCBI genotype: 7099), TLR5 (NCBI genotype: 7100), TLR6 (NCBI genotype: 10333), TLR7 (NCBI genotype: 51284), TLR8 (NCBI genotype: 51311), TLR9 (NCBI genotype: 54106), and / or TLR10 (NCBI genotype: 81793).Examples of TLR7 agonists that can be co-administered include (but are not limited to) AL-034, DSP-0509, GS-9620 (vesamimod), vesamimod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, remiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, limoutope, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795 and compounds disclosed in the following cases: US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences) and US20090047249 (Gilead Sciences). Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx The patents registered with Ventrilo Pharma (US20120219615), Ventrilo Pharma (US20140066432), Ventrilo Pharma (US20140088085), Novira Therapeutics (US20140275167), and Novira Therapeutics (US20130251673) are listed. TLR7 / TLR8 agonists include (but are not limited to) NKTR-262, teiramod, and BDB-001.TLR8 agonists include (but are not limited to) E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motomod, remiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052 and compounds disclosed in the following cases: US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics). TLR9 agonists include (but are not limited to) AST-008, cobitopomod, CMP-001, IMO-2055, IMO-2125, S-540956, ritomod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, atorvastatin, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefemod (MGN-1703), CYT-003, CYT-003-QbG10, tilosomod, and PUL-042. Examples of TLR3 agonists include rapamod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. TLR4 agonists include (but are not limited to) G-100 and GSK-1795091. CDK inhibitors or antagonists

[0335] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with CDK inhibitors or antagonists. In some embodiments, the CDK inhibitors or antagonists are selected from the group consisting of VS2-370. STING agonists, RIG-I and NOD2 modulators

[0336] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with interferon gene stimulating factor (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of: ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, STING agonist (latent HIV), 5,6-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP. In some embodiments, the agents described herein are combined with RIG-1 modulators (e.g., RGT-100) or NOD2 modulators (e.g., SB-9200 and IR-103). LAG-3 and TIM-3 inhibitors

[0337] In some embodiments, compounds as described herein or pharmaceutically acceptable salts thereof are combined with anti-TIM-3 antibodies (e.g., TSR-022, LY-3321367, MBG-453, INCAGN-2390).

[0338] In some embodiments, the antibody or antigen-binding fragment described herein is combined with an anti-LAG-3 (lymphocyte activation gene) antibody (e.g., renalalimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385). interleukin agonists

[0339] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one interleukin agonist. In some embodiments, the agents described herein are combined with interleukin agonists (e.g., IL-2, IL-7, IL-15, IL-10, IL-12 agonists); examples of IL-2 agonists include (e.g.) prazolam (aldeleukin, IL-2), BC-IL (Cel-Sci), polyethylene glycol-modified IL-2 (e.g., NKTR-214), IL-2 modified variants (e.g., THOR-707), bepecide-aldeleukin, AIC-284, ALKS-4230, CUI-101, Neo-2 / 15; examples of IL-15 agonists include (e.g.) Examples of IL-7 include (but are not limited to) ALT-803, NKTR-255 and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 soinholm (polyethylene glycolated IL-15), P-22339 and IL-15-PD-1 fusion protein N-809; examples of IL-7 include (but are not limited to) CYT-107.

[0340] Examples of other immunotherapy-based treatments that can be combined with the pharmaceutical agents of the present invention include (but are not limited to) interferon α, interferon α-2b, interferon α-n3, pegylated interferon α, interferon γ, FLT3 agonists (e.g., CDX-301), GS-3583, gaprox, nifedipine, pegylated interferon α-2a, pegylated interferon α-2b, and RPI-MN. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0341] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one PI3K inhibitor. Examples of PI3K inhibitors include ederaris, apacilipes, bupparis, CAI orotate, coupannis, duveris, godatoris, neratinib, panulisex, perifoxine, picoxib, piracetam, praquitinib mesylate, regoracitinib, regoracitinib sodium, sonicoxib, tasecoxib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, and EN-33. 42. GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474. α-4 / β-7 antagonists

[0342] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one α-4 / β-7 antagonist. Examples of integrin α-4 / β-7 antagonists include PTG-100, TRK-170, alilumab, erolizumab, methylcarograss, and vedolizumab. HIV antibodies, bispecific antibodies, and antibody-like therapeutic proteins

[0343] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HIV antibody, a bispecific antibody, and an "antibody-like" therapeutic protein. Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bispecific antibodies, trispecific antibodies, multivalent antibodies, bNAb (broadly neutralizing HIV antibody), BMS-936559, TMB-360 and antibodies targeting HIV gp120 or gp41, HIV-targeting antibody recruitment molecules, anti-CD63 monoclonal antibodies, CD3 bispecific antibodies, CD16 bispecific antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibodies, camel-derived anti-CD18 antibodies, camel-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAb (PGT-121), elbalizumab, Imgro, and MB-66. Other examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include (but are not limited to) gp120 bispecific monoclonal antibody, PCT121.414.LS, elbalizumab (second generation), pure human monoclonal antibody targeting KLIC (HIV infection), GS-9721, BG-HIV, VRC-HIVMAB091-00-AB, and combinations thereof.

[0344] Various bNAbs can be used. Examples include (but are not limited to) those described in U.S. Patents 8,673,307, 9,493,549, 9,783,594, 10,239,935, US2018371086, US2020223907, WO2014 / 063059, WO2012 / 158948, WO2015 / 117008, PCT / US2015 / 41272, and WO2017 / 096221, including antibodies 12A12, 12A21, NIH45-46, bANC131, 8ANC134, IB2530, INC9, 8ANC195, 8ANC196, 10-259, 10-303, 10-410, 10- 847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369 and 10-1074GM. Other examples include (but are not limited to) those described in the following literature: Klein et al., Nature, 492(7427): 118-22 (2012); Horwitz et al., Proc Natl Acad Sci USA, 110(41): 16538-43 (2013); Scheid et al., Science, 333: 1633-1637 (2011); Scheid et al., Nature, 458:636-640 (2009); Eroshkin et al., Nucleic Acids Res., 42 (database issue number):Dl 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E81 (All bind to gp41 MPER); PG9, PG16, CH01-04 (all bind to V1V2-glycan), 2G12 (which binds to the outer domain glycan); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176 and 8ANC131 (all bind to CD4 binding sites).

[0345] Other broadly neutralizing antibodies that can be used as a second therapeutic agent in combination therapy are described, for example, in the following cases: U.S. Patents 8,673,307, 9,493,549, and 9,783,594; and WO 2012 / 154312; WO2012 / 158948; WO 2013 / 086533; WO 2013 / 142324; WO2014 / 063059; WO 2014 / 089152; WO 2015 / 048462; WO 2015 / 103549; WO 2015 / 117008; WO2016 / 014484; WO 2016 / 154003; WO 2016 / 196975; WO 2016 / 149710;WO2017 / 096221;WO 2017 / 133639;WO 2017 / 133640, the entire contents of which are incorporated herein by reference for all purposes. Other examples include those described in the following literature: Sajadi et al., Cell. (2018) 173(7):1783-1795; Sajadi et al., J Infect Dis. (2016) 213(1):156-64; Klein et al., Nature, 492(7427): 118-22 (2012); Horwitz et al., Proc Natl Acad Sci USA, 110(41): 16538-43 (2013); Scheid et al., Science, 333: 1633-1637 (2011); Scheid et al., Nature, 458:636-640 (2009); Eroshkin et al., Nucleic Acids Res., 42 (database issue number):Dl 133-9 (2014); Mascola et al., Immunol Rev., 254(l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074 and LN01 (all MPERs bound to gp41).

[0346] Other examples of antibodies include (but are not limited to) BF520.1, BiIA-SG, CH01, CH59, CAP256V2LS, DH270.1, DH270.6, D1D2, Cl3hmAb, and GS-9722. (elipovimab), BG18, GS-9721, GS-9723, PGT145, PGT121, PGT-121.60, PGT-121.66, PGT122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT-139, DH511-2, N49P7.1, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (Ipilimumab), VRC01, VRC-01-LS, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, IMC-HIV, iMabm36, eCD4-Ig, IOMA, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC29.03, C AP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34 and VRC34.01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2 and LN01.Examples of HIV-targeting drugs in this manner include bavitimab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC117-LS, 3BNC60, 10-1074, 10-1074-LS, GS-9722, DH411-2, PGT145, PGT121, PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, N6LS, N49P6, N49P7, N49P9, N49P11, and VRC01. VRC-01-LS, PGDM1400, A32, 7B2, 10E8, 10E8VLS, 3810109, 10E8v4, CAP256-VRC26.25, DRVIA7, SAR-441236, VRC-07-523, VRC07-523LS, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, and VRC07. Examples of HIV bispecific antibodies include MGD014 and TMB-bispecific. Examples of HIV bispecific and trispecific antibodies include (but are not limited to) MGD014, B12BiTe, BiIA-SG, TMB-bispecific, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, 10E8v4 / PGT121-VRC01, and combinations thereof.

[0347] Examples of in vivo delivered bNAbs include, for example, AAV8-VRC07 and the anti-HIV antibody VRC01 encoding mRNA. Other examples of in vivo delivered bNAbs include modified B cells encoding 3BNC117 (Hartweger et al., J. Exp. Med. 2019, 1301). Pharmacokinetic enhancers

[0348] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one pharmacokinetic enhancer. Examples of pharmacokinetic enhancers include crobisstat and ritonavir. Other treatments

[0349] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one other therapeutic agent. Examples of other therapeutic agents include compounds disclosed in the following cases: WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan The entire contents of each of the following patents are incorporated herein by reference: Tobacco, WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences), WO 2013 / 091096 (Boehringer Ingelheim), WO 2018 / 145021 (Gilead Sciences), and WO2017 / 106346 (Gilead Sciences). HIV vaccine

[0350] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HIV vaccine. Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV subtype C vaccine, Remnoliptin, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multibranched DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, and NAcGM3 / VSSP. ISA-51, Poly-ICLC Adjuvanted Vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[δ]V2.TV1+MF-59, rVSVIN HIV gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV, Ad-4 (Ad4-env Clade) C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines (e.g., pseudoviral vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugated peptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-2010, gp41 HIV vaccine, HIV vaccine (PIKA adjuvant), I i-key / MHC class II epitope heterozygous peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-branched Env vaccine, MVA vaccine, Pennvax-GP, pp71 defective HCMV vector HIV GAG vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romedixin, variant gp120 peptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; vaccines based on eOD-GT8 60-mer, PD-201401, env (A,B,C,A / E) / gag (C) DNA vaccine, gp120 (A,B,C,A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV vaccine (GLA-SE adjuvanted), HIV p24gag primiparous-booster plasmid DNA vaccine, immunotherapies based on isoplasmic virus vectors (Vaxwave, TheraT), MVA-BN HIV vaccine regimen, UBI HIV gp120, mRNA-based preventive vaccines, and TBL-1203HI. Other examples of HIV vaccines include (but are not limited to) HIV MAG DNA vaccines, adenovirus vector vaccines (adenovirus vectors, such as Ad5, Ad26, or Ad35), simian adenovirus (chimpanzee, gorilla, rhesus monkey (i.e., rhAd)), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), Coxsackievirus-based vaccines, enterovirus-based vaccines, gorilla adenovirus vaccines, lentiviral vector-based vaccines, arenavirus vaccines (e.g., LCMV, Pichind), bisegmental or trisegmental arenavirus-based vaccines, trimer-based HIV-1 vaccines, measles virus-based vaccines, flavivirus-based vaccines, tobacco mosaic virus-based vaccines, varicella-zoster virus-based vaccines, and human parainfluenza virus-based vaccines. (PIV3) vaccines, poxvirus-based vaccines (modified Ankara cowpox virus (MVA), orthopoxvirus-derived NYVAC, and avianpoxvirus-derived ALVAC (canarypox virus strain); fowlpox virus-based vaccines, rod-shaped virus-based vaccines (e.g., VSV and Malabar virus); recombinant human CMV (rhCMV)-based vaccines, and alphavirus-based vaccines (e.g., Semliki forest virus, Venezuelan equine encephalitis virus, and Syndebes virus); (See Lauer, Clinical and Vaccine Immunology, 2017). [DOI:]10.1128 / CVI.00298-16); Therapeutic vaccines based on LNP-regulating mRNA; LNP-regulating self-replicating RNA / self-amplifying RNA vaccines and combinations thereof. Examples of other vaccine agents include (but are not limited to) AAVLP-HIV vaccine, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664 gp140 adjuvanted vaccine, BG505 SOSIP.GT1.1 gp140 adjuvanted vaccine, ChAdOx1.tHIVconsv1 vaccine, CMV-MVA trivalent vaccine, ChAdOx1.HTI, Chimigen HIV vaccine, ConM SOSIP.v7 gp140, MPER-656 liposomal subunit vaccine, Pennvax-G / MVA-CMDR, ChAdV63.HIVconsv, SeV-EnvF, HIV vaccine based on N123-VRC-34.01 inducible epitope, GOVX-C55, TVI-HIV-1, ENOB-HV-11, ENOB-HV-12, MagaVax, DNA and Sev vector vaccines expressing SCaVII, VIR-1111, DermaVir, HIV-1 iglb12 neutralizing VRC-01 antibody-stimulated anti-CD4 vaccine, arenavirus-based vector vaccine, VPI-211, multimeric HIV gp120 vaccine (Fred Hutchinson Cancer Center) and combinations thereof. Contraception combination therapy

[0351] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one contraceptive or sterilization regimen. Therapeutic agents for contraception that can be combined with the agents of the present invention include (but are not limited to) cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, diethylstilbestrol, norethindrone, etoposide, L-5-methyltetrahydrofolate, levonorgestrel, linegestrel, medroxyprogesterone acetate, mestriol, mifepristone, misoprostol, noremexone acetate, methylprogesterone acetate, norethindrone, isethindrone, norethindrone ester, olmexifen, sigmason acetate, ulipristal acetate, and any combination thereof. HIV combination therapy

[0352] In a particular embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with one, two, three, four or more other therapeutic agents selected from the following: ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bicitilavir, tenofovir alafenamide, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (erticavir, crobistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF + FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (Tenofovir elastin, emtricitabine, clobistat, and erlotinib); Adefovir; Adefovir dipivoxel; Clobistat; Emtricitabine; Tenofovir; Tenofovir disoproxil fumarate; Tenofovir disoproxil fumarate; Tenofovir elastin; Tenofovir hemifumarate; TRIUMEQ® (drogher, abacavir, and lamivudine); Drogher, abacavir sulfate, and lamivudine; Rettagvir; Rettagvir and lamivudine; Maraviro; Enfuvir peptide; ALUVIA® (KALETRA®; Lopinavir and ritonavir); COMBIVIR® (Zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; Abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and crombistarta; Atazanavir and crombistarta; Darunavir and crombistarta; Atazanavir; Atazanavir sulfate; Derogerovir; Eticagvir; Ritonavir; Atazanavir sulfate and Ritonavir; Darunavir; Lamivudine; Prosine; Furazanal Viagra; Furazanavir Calcium - Efaviren; Etravirine; Nafenavir; Nafenavir Mesylate; Interferon; Doxorinosine; Stavudine; Indinavir; Indinavir Sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir Mesylate; Aldehyde; Zaxitabine; Telanavir; Ampronavir; Dilaviridine; Dilaviridine Mesylate; Radha-108 (Lexiter); Lamivudine and Tenofovir Disoproxil Fumarate; Efaviren, Lamivudine and Tenofovir Disoproxil Fumarate; Aziphosphonate; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir Sulfate.Other treatment options include (for example) tenofovir alafenamide and erlotinib; tenofovir alafenamide + erlotinib (rectal preparation, HIV infection); pegylated retegvir; lamivudine + lopinavir + ritonavir + abacavir; tenofovir + emtricitabine + maraviroxine and combinations thereof.

[0353] Those familiar with this technique will understand that the other therapeutic agents listed above may be included in more than one of the categories listed above. The specific category is not intended to limit the functionality of the compounds listed in those categories.

[0354] In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor. In another specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV non-nucleoside reverse transcriptase inhibitor. In another specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV protease inhibitor. In yet another embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In yet another embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two HIV nucleoside or nucleotide reverse transcriptase inhibitors. In one specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleoside or nucleotide reverse transcriptase inhibitors and HIV capsid inhibitors or HIV capsid polymerization inhibitors. In one specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV capsid inhibitors or HIV capsid polymerization inhibitors. In one specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with one, two, three, or four HIV bNAbs. In one specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with one, two, three, or four HIV bNAbs and HIV capsid inhibitors or HIV capsid polymerization inhibitors. In one specific embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with one, two, three, or four HIV bNAbs, HIV capsid inhibitors or HIV capsid polymerization inhibitors, and HIV nucleoside or nucleotide reverse transcriptase inhibitors. In another embodiment, the compound disclosed herein or a pharmaceutical composition thereof is combined with two HIV nucleoside or nucleotide reverse transcriptase inhibitors. Gene therapy and cell therapy

[0355] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with gene or cell therapy regimens. Gene and cell therapies include (but are not limited to) gene modification to silence genes; gene-based methods of directly killing infected cells; designing infusions of immune cells to replace most of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to seek out and kill infected cells; and gene-based methods of modifying cell activity to further alter the endogenous immune response to infection. Examples of cell therapies include (but are not limited to) LB-1903, ENOB-HV-01, ENOB-HV-31, GOVX-B01, HSPC overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapies. Examples of dendritic cell therapies include (but are not limited to) AGS-004. CCR5 gene editing agents include (but are not limited to) SB-728T and SB-728-HSPC. CCR5 gene inhibitors include (but are not limited to) Cal-1 and autologous CD34-positive hematopoietic progenitor cells (HIV-infected / HIV-related lymphoma) transduced with lentiviral vector CCR5 shRNA / TRIM5α / TAR decoys. In some embodiments, CD4-positive T cells expressing C34-CCR5 / C34-CXCR4 are co-administered with one or more multispecific antigen-binding molecules. In some embodiments, the agents described herein are co-administered with autologous T-cell therapy transduced with AGT-103 or AAV-eCD4-Ig gene therapy. Gene editing agents

[0356] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with gene-editing agents (e.g., HIV-targeting gene-editing agents). In various embodiments, the gene editing system may be selected from the group consisting of: CRISPR / Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing nuclease complexes, and large-scale nuclease complexes. Elucidating HIV-targeting CRISPR / Cas9 systems include (but are not limited to) EBT-101. CAR-T cell therapy

[0357] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof may be co-administered with a population of immune effector cells modified to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen-binding domain. The HIV antigen includes HIV mantle protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4 inducible binding site on gp120, N-glycans on gp120, V2 of gp120, and a membrane-adjacent region on gp41. The immune effector cell line is a T cell or NK cell. In some embodiments, the T cell line is a CD4+ T cell, a CD8+ T cell, or a combination thereof. The cells may be autologous or allogeneic. Examples of HIV CAR-T include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CAR-T, anti-HIV duoCAR-T, anti-CD4 CAR-T cell therapy, CD4 CAR+C34-CXCR4+CCR5 ZFN T cells, anti-CD4 MicAbody antibody + anti-MicAbody CAR T cell therapy (iNKG2D CAR, HIV infection), GP-120 CAR-T therapy, and autologous hematopoietic stem cells genetically modified to express CD4 CAR and C46 peptide. TCR T-cell therapy

[0358] In some embodiments, compounds described herein or pharmaceutically acceptable salts thereof are combined with a population of TCR-T cells. TCR-T cells are modified to target HIV-derived peptides, such as ImmTAV, present on the surface of virus-infected cells. B-cell therapy

[0359] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one B-cell therapy. In some embodiments, the antibodies or antigen-binding fragments described herein are combined with a population of B cells genetically modified to express broadly neutralizing antibodies (e.g., 3BNC117) (Hartweger et al., J. Exp. Med. 2019, 1301; Moffett et al., Sci. Immunol. 4, eaax0644 (2019), May 17, 2019).

[0360] The compounds disclosed herein (e.g., any Formula I compound) can be combined with one, two, three, or four other therapeutic agents at any dosage of Formula I compound (e.g., 1 mg to 500 mg of compound).

[0361] In one embodiment, a kit is provided comprising a combination of the compound disclosed herein or a pharmaceutically acceptable salt thereof with one or more (e.g., one, two, three, one or two, or one to three) other therapeutic agents.

[0362] In one embodiment, one or more other therapeutic agents or pharmaceuticals in the kit are selected from the following anti-HIV agents: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosite) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (e.g., CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (e.g., chimeric antigen receptor T cells (CAR-T) and modified T cell receptors (TCR-T), autologous T cell therapy), latency reversal agents, compounds targeting the HIV capsid, capsid polymerization inhibitors, HIV bNAb, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infection factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, protein 1 modulators containing COMM domains, HIV ribonuclease H inhibitors, resveratrol modulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines and combinations thereof.

[0363] In some embodiments, one or more other therapeutic agents in the kit are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allotropic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immunotherapy-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0364] In one specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide reverse transcriptase inhibitor. In another specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV non-nucleoside reverse transcriptase inhibitor. In another specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, and an HIV protease inhibitor. In yet another embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In some embodiments, the kit includes at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer, a compound disclosed herein or a pharmaceutically acceptable salt thereof. In yet another embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and two HIV nucleoside or nucleotide reverse transcriptase inhibitors. In one specific embodiment, the kit includes the compounds disclosed herein or pharmaceutically acceptable salts thereof, HIV nucleoside or nucleotide reverse transcriptase inhibitors, and HIV capsid inhibitors or HIV capsid polymerization inhibitors. In one specific embodiment, the kit includes the compounds disclosed herein or pharmaceutically acceptable salts thereof, and HIV capsid inhibitors or HIV capsid polymerization inhibitors. In one specific embodiment, the kit includes the compounds disclosed herein or pharmaceutically acceptable salts thereof, and one, two, three, or four HIV bNAbs. In one specific embodiment, the kit includes the compounds disclosed herein or pharmaceutically acceptable salts thereof, one, two, three, or four HIV bNAbs, HIV capsid inhibitors or HIV capsid polymerization inhibitors. In one specific embodiment, the kit includes the compounds disclosed herein or pharmaceutically acceptable salts thereof, one, two, three, or four HIV bNAbs, HIV capsid inhibitors or HIV capsid polymerization inhibitors, and HIV nucleoside or nucleotide reverse transcriptase inhibitors. In one specific embodiment, the kit includes the compounds disclosed herein or their pharmaceutically acceptable salts, HIV nucleoside reverse transcriptase inhibitors, and HIV capsid inhibitors. Contraception combination therapy

[0365] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one contraceptive combination therapy. Therapeutic agents for contraception include cyproterone acetate, desogestrel, dinogest, drospirenone, estradiol valerate, ethylene estradiol, norethindrone, etoposide, L-5-methyltetrahydrofolate, levonorgestrel, linegestrel, medroxyprogesterone acetate, mestriol, mifepristone, misoprostol, noremexone acetate, methylprogesterone acetate, norethindrone, isethindrone, norethindrone, olmexifen, sigmazoline acetate, ulipristal acetate, and any combination thereof. Gene therapy and cell therapy

[0366] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one gene and / or cell therapy. Gene and cell therapies include: gene modification to silence genes; gene-mediated methods of directly killing infected cells; designing the infusion of immune cells to replace most of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to locate and kill infected cells; and gene-mediated methods of modifying cell activity to further alter the endogenous immune response to infection.

[0367] Examples of dendritic cell therapy include AGS-004.

[0368] Examples of CCR5 gene-editing drugs include SB-728T.

[0369] Examples of CCR5 gene inhibitors include Cal-1. Gene editing agents

[0370] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one gene-editing agent. The gene editing system is selected from the group consisting of: CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing nuclease systems, and large-scale nuclease systems.

[0371] Examples of CRISPR / Cas9 systems targeting HIV include EBT-101. CAR-T cell therapy

[0372] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one CAR-T cell therapy. An immune effector cell population modified to express a chimeric antigen receptor (CAR), wherein the CAR includes an HIV antigen-binding domain. The HIV antigen includes HIV mantle protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4 inducible binding site on gp120, N-glycan on gp120, V2 of gp120, and a membrane-adjacent region on gp41. Immune effector cell lines are T cells or NK cells. In some embodiments, the T cell line is CD4+ T cells, CD8+ T cells, or a combination thereof. The cells may be autologous or allogeneic.

[0373] Examples of HIV CAR-T include VC-CAR-T, anti-CD4 CART cell therapy, and autologous hematopoietic stem cells that are genetically modified to express CD4 CAR and C46 peptide. TCR-T cell therapy

[0374] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one TCR-T cell therapy. TCR-T cells are modified to target HIV-derived peptides present on the surface of virus-infected cells. Long-term HIV therapy

[0375] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one long-acting HIV therapy. Examples of drugs being developed as long-acting regimens include carboplatinavir, rilpivirine, any integrase LA, VM-1500 LAI, maraviro (LAI), tenofovir implant, MK-8591 implant, doravirine, retegvir, and long-acting derogvir. HBV combination therapy

[0376] In some embodiments, a method for treating or preventing HBV infection in humans who are infected or at risk of such infection is provided, comprising administering to a human a therapeutically effective amount of the composition described herein and a combination of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents. In one embodiment, a method for treating HBV infection in humans who are infected or at risk of such infection is provided, comprising administering to a human a therapeutically effective amount of the composition described herein and a combination of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents.

[0377] In some embodiments, a pharmaceutical composition is provided comprising a combination of the compound of the present invention or a pharmaceutically acceptable salt thereof with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents and pharmaceutically acceptable excipients.

[0378] In some embodiments, kits are provided that comprise a combination of the compound of the present invention or a pharmaceutically acceptable salt thereof with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents.

[0379] In some embodiments, the pharmaceutical agent of the present invention or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more other therapeutic agents. In some embodiments, the pharmaceutical agent of the present invention or a pharmaceutically acceptable salt thereof is combined with two other therapeutic agents. In some embodiments, the pharmaceutical agent of the present invention or a pharmaceutically acceptable salt thereof is combined with three other therapeutic agents. In some embodiments, the pharmaceutical agent of the present invention or a pharmaceutically acceptable salt thereof is combined with four other therapeutic agents. The one, two, three, four, or more other therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or may be selected from different classes of therapeutic agents.

[0380] In some embodiments, when combining the pharmaceutical agents of the present invention with one or more other therapeutic agents as described herein, the components of the composition are administered in a simultaneous or sequential manner. In sequential administration, the combination may be administered two or more times.

[0381] Co-administration of the drug disclosed herein and one or more other therapeutic agents generally means administering the drug disclosed herein and one or more other therapeutic agents simultaneously or sequentially, so that a therapeutically effective amount of each drug is present in the patient's body.

[0382] Co-doping includes administering a unit dose of the agent disclosed herein before or after administering a unit dose of one or more other therapeutic agents. The agent disclosed herein may be administered within seconds, minutes, or hours after administering one or more other therapeutic agents. For example, in some embodiments, a unit dose of the agent disclosed herein is administered first, followed by a unit dose of one or more other therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of the agent disclosed herein within seconds or minutes. In some embodiments, a unit dose of the agent disclosed herein is administered first, followed by a unit dose of one or more other therapeutic agents after a period of several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of the agent disclosed herein after a period of several hours (e.g., 1-12 hours).

[0383] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with one or more other therapeutic agents in a single dosage form for simultaneous administration to a patient, such as in a solid dosage form for oral administration.

[0384] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with one, two, three, four or more other therapeutic agents selected from: HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, TLR receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis B core antigen (HBcAg) inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi agents, endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, and covalently closed circular DNA. (cccDNA) inhibitors, farnesoid X receptor agonists, STING agonists, anti-HBV antibodies, CCR2 chemokine antagonists, caspase-9 stimulators, CD3 modulators, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, ZCCHC14 inhibitors, tertiary lymphoid aggregate inducers, nucleic acid polymers (e.g., NAP and STOPS), PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin α-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginine inhibitors, gene therapy and cell therapy, gene editing agents, CAR-T cell therapy, TCR-T cell therapy, other HBV drugs and combinations thereof. In some embodiments, this description provides a method of treating HBV infection comprising administering to a patient in need a therapeutically effective amount of the composition described herein combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents suitable for treating HBV infection.

[0385] The compounds described herein may be used or combined with one or more of the following: chemotherapeutic agents, immunomodulators, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies and "antibody-like" therapeutic proteins (e.g., DARTs®, Duobodies®, Bits®, XmAbs®, TandAbs®, Fab derivatives), antibody-drug conjugates (ADCs), gene modifiers or gene editing agents (e.g., CRISPR Cas9, zinc finger nucleases, homing intracellular nucleases, synthetic nucleases, TALEN), cell therapies (e.g., CAR-T (chimeric antigen receptor T cell) and TCR-T (modified T cell receptor) agents) or any combination thereof. Other examples include (but are not limited to) DARPins®, anti-pMHC TCR-like antibodies, homing broad-spectrum nucleases (e.g., ARCUS), and combinations thereof.

[0386] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with one, two, three, four or more other therapeutic agents, such other therapeutic agents being (e.g.) 3-dioxanone (IDO) inhibitors, apolipoprotein A1 modulators, arginine inhibitors, B- and T lymphocyte attenuation protein inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, compounds targeting hepatitis B core antigen (HBcAg), core protein allotope modulators, covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, postgenetic modifiers, farnesol X receptor agonists, free fatty acid (Ffa) receptor 2 (Ffar2;PR43) agonists, and free fatty acid (Ffa) receptor 3 (Ffar3;PR43) agonists.GPR441 agonist, HBV DNA polymerase inhibitor, HBV replication inhibitor, HBV RNAse inhibitors, HBV virus entry inhibitors, HBx inhibitors, hepatitis B mantle protein inhibitors, hepatitis B mantle protein stimulators, hepatitis B structural protein modulators, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitors, HIV-1 reverse transcriptase inhibitors, hyaluronidase inhibitors, apoptosis protein family (IAP) protein inhibitors, IL-2 agonists, IL-7 agonists, immunomodulators, indoleamine-2 inhibitors, ribonucleotide reductase inhibitors, interleukin-2 ligands, ipi4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, lymphocyte-activated gene 3 inhibitors, lymphotoxin β receptor activators, Axl modulators, B7-H 3. Regulators, B7-H4 regulators, CD160 regulators, CD161 regulators, CD27 regulators, CD47 regulators, non-standard RNA polymerase PAPD5 inhibitors, non-standard RNA polymerase PAPD7 inhibitors, CD70 regulators, GITR regulators, HEVEM regulators, ICOS regulators, Mer regulators, NKG2A regulators, NKG2D regulators, OX40 regulators, SIRPα regulators, TIGIT regulators, Tim-4 regulators, Tyro regulators, Na+-taurocholic acid cotransporter (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nucleoprotein regulators, OX-40 receptor agonists, PD-1 inhibitors, PD-L1 inhibitors, peptidylprolyl isomerase inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, retinoic acid-inducible gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNA DNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimics, Src tyrosine kinase inhibitors, interferon gene stimulating factor (STING) agonists, NOD1 stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 regulators, thymosin agonists, thymosin α1 ligands, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-7 regulators, TLR-8 regulators, TLR-9 agonists, TLR9 agonists or gene stimulators, TLR receptor (TLR) regulators, viral ribonucleotide reductase inhibitors, and combinations thereof. HBV combination therapy

[0387] In some embodiments, the compounds described herein are combined with at least one combination therapy for the treatment of HBV. Examples of combination therapies for the treatment of HBV include TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine and PEG-IFN-α; ABX-203 adefovir and PEG-IFNα; and INO-1800 (INO-9112 and RG7944). Other HBV medications

[0388] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one other HBV drug. Examples of other drugs for the treatment of HBV include α-hydroxytophenone, Adorviry, β-hydroxycytosine nucleoside, AL-034, CCC-0975, evitabine, ezetimibe, cyclosporine A, gentiopicrin, JNJ-56136379, nitrozonide, bispyribacylpyridinium chloride, NJK14047, NOV-205 (Morishane, BAM-205), oligosaccharide, mirtovalidone, ferroenylpyridinium chloride, GST-HG-131, levamisole, Ka Shu Ning, arofilone, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, and cTP-5. (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IPB-006IA, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, berberine, DasKloster-0039, heprantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551 and ZH-2N, as described in US20150210682, (Roche), US 2016 / 0122344 (Roche), WO2015173164, WO2016023877, US2015252057A The compounds listed in (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche) and US2015031687A (Roche).Other examples of other medications used to treat HBV include (but are not limited to) antroquinonol, ARB-199, ccc-R08, HH-003, hepalatide, NCO-48 fumarate, XTYW-001, SFA-001, ENOB-HB-01, QL-007, sofosbuvir, ledipasvir, PA-1010, HPN-BV1, STSG-0002, and combinations thereof. HBV vaccine

[0389] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HBV vaccine. HBV vaccines include preventative vaccines and therapeutic vaccines. Examples of HBV preventative vaccines include Vaxelis, Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D / T / P / HBV / M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, Advax Super D (Hepatitis B preventative vaccine), Hepatrol-07, GSK-223192A, ENGERIX B®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenula polymorpha yeast, intramuscular, Hualan Biological Engineering), recombinant hepatitis B surface antigen vaccine, Bimmugen, Eufovac, Eutravac, and Anrix-DTaP-IPV-Hep. B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan5, Shan6, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa and DTaP-rHB-Hib vaccine. Other vaccines include (but are not limited to) CARG-101, YS-HBV-001, IR-101H, TVAX-008, and combinations thereof.

[0390] Examples of therapeutic HBV vaccines include HBsAG-HBIG complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (εPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500, HBVax, im / TriGrid / antigen vaccine, Mega-CD40L-adjuvanted vaccine, HepB-v, RG7944 (INO-1800), and recombinant VLP-based therapeutic vaccines (HBV infection, VLP). Biotech), AdTG-17909, AdTG-17910, AdTG-18202, ChronVac-B, TG-1050 and Lm HBV. Other examples of therapeutic HBV vaccines include (but are not limited to) HepTcell, therapeutic DNA vaccines for hepatitis B, VVX-001, GSK-3528869A (ChAd155-hli-HBV + MVA-HBV + Hbc-HBs / AS01B-4), VBI-2601, VTP-300 (ChAdOx1-SIi-HBV-CPmut-TPA-Ssh primary immunization and MVA-SIi-HBV-CPmut-TPA-Ssh booster), MVA-BN, AVA-2100, HBV-ADV311, YS-HBV-002, HBV isovirus vaccines (disclosed in, for example, WO2017076988 and WO2017198726) and combinations thereof. HBV DNA polymerase inhibitors

[0391] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is combined with at least one HBV DNA polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, besfovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), feloxivir (filocilovir), paradefovir, clavidine, ribavirin, and lamivudine (EPIVIR-HBV). ®), azidophosphine, famciclovir, forsoline, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil fumarate aspartate, tenofovir disoproxil fumarate orotate, and HS-10234. Other examples of HBV DNA polymerase inhibitors include (but are not limited to) tenofovir exalidex, ATI-2173, AiB-001, and combinations thereof. Immunomodulators

[0392] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one immunomodulator. Examples of immunomodulators include rapamod, imidrol hydrochloride, ingaron, dermaVir, hydroxychloroquine sulfate tablets (hydroxychloroquine), prazolam, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), JNJ-440, WF-10, AB-452, ribavirin, IL-12, INO-9112, polymeric polyethyleneimine (PEI), guapentin, VGV-1, MOR-22, CRV-431, JNJ-0535, TG-1050, ABI-H2158, BMS-936559, GS-9688, RO-7011785, RG-7854, AB-506, RO-6871765, AIC-649, and IR-103. TLR receptor modulators

[0393] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with agonists of TLR receptors (TLRs), such agonists being, for example, agonists of TLR1 (NCBI genotype: 7096), TLR2 (NCBI genotype: 7097), TLR3 (NCBI genotype: 7098), TLR4 (NCBI genotype: 7099), TLR5 (NCBI genotype: 7100), TLR6 (NCBI genotype: 10333), TLR7 (NCBI genotype: 51284), TLR8 (NCBI genotype: 51311), TLR9 (NCBI genotype: 54106) and / or TLR10 (NCBI genotype: 81793), TLR11, TLR12 and TLR13. TLR modifiers include modifiers for TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 and TLR13.

[0394] Examples of TLR3 modifiers include rapamod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0395] Examples of TLR modifiers include (but are not limited to) AK-0701.

[0396] Examples of TLR4 modifiers include (but are not limited to) G-100 and GSK-1795091.

[0397] Examples of TLR7 modulators include GS-9620 (vesamimod), GSK-2245035, imiquimod, remiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, limoutop, D, teiramod, SP-0509, TMX-30X, TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and compounds described in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences). Other examples of TLR7 modulators include (but are not limited to) AL-034, DSP-0509, LHC-165, TMX-101 (imiquimod) and combinations thereof.

[0398] Examples of TLR8 modulators include motomodil, remiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, GS-9688, and compounds described in the following cases: US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US Patent No. 9670205, US20160289229, US Patent Application No. 15 / 692161 and US Patent Application No. 15 / 692093.

[0399] TLR7 / TLR8 modifiers include (but are not limited to) NKTR-262, teiramod, and BDB-001.

[0400] Examples of TLR-8 inhibitors include (but are not limited to) ZG-170607.

[0401] Examples of TLR8 agonists include (but are not limited to) E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motomod, requimide, selgantolimod (GS-9688), HRS-9950, VTX-1463, VTX-763, 3M-051, 3M-052 and compounds disclosed in the following cases: US2016289229 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US Patent No. 9670205 (Gilead Sciences, Inc.), US20160289229 (Gilead Sciences, Inc.), WO2017 / 048727 (Gilead Sciences, Inc.), US20180065938 (Gilead Sciences, Inc.) and US20180086755 (Gilead Sciences, Inc.).

[0402] Examples of TLR9 modifiers include BB-001, BB-006, CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, Atorvastatin, DIMS-9054, DV-1079, DV-1179, AZD-1419, Lefebvril (MGN-1703), Litamod, and CYT-003-QbG10. Other examples of TLR9 modifiers include AST-008, Copitoporvastatin, CMP-001, S-540956, Litamod, MGN-1601, BB-001, BB-006, CYT-003, Tilosomostatin, PUL-042, and combinations thereof.

[0403] Examples of TLR7, TLR8, and TLR9 modulators include compounds described in the following cases: WO2017047769 (Teika Seiyaku), WO2015014815 (Janssen), WO2018045150 (Gilead Sciences Inc), WO2018045144 (Gilead Sciences Inc), WO2015162075 (Roche), WO2017034986 (University of Kansas), WO2018095426 (Jiangsu Hengrui Medicine Co Ltd), WO2016091698 (Roche), WO2016075661 (GlaxoSmithKline Biologicals), WO2016180743 (Roche), WO2018089695 (Dynavax Technologies), WO2016055553 (Roche), WO2015168279 (Novartis), WO2016107536 (Medshine Discovery), WO2018086593 (Livo (Shanghai) Pharmaceutical), WO2017106607 (Merck), WO2017061532 (Sumitomo Dainippon Pharma), WO2016023511 (Chia Tai Tianqing Pharmaceutical), WO2017076346 (Chia Tai Tianqing Pharmaceutical), WO2017046112 (Roche), WO2018078149 (Roche), WO2017040233 (3M Co), WO2016141092 (Gilead Sciences), WO2018049089 (Bristol Myers) Squibb), WO2015057655 (Eisai Co Ltd), WO2017001307 (Roche), WO2018005586 (Bristol Myers Squibb), WO201704023 (3M Co), WO2017163264 (Council of Scientific and Industrial Research (India)), WO2018046460 (GlaxoSmithKlineBiologicals), WO2018047081 (Novartis), WO2016142250 (Roche), WO2015168269 (Novartis), WO201804163 (Roche), WO2018038877 (3M Co), WO2015057659 (Eisai Co Ltd), WO2017202704 (Roche), WO2018026620 (Bristol Myers Squibb), WO2016029077 (Janus Biotherapeutics), WO201803143 (Merck), WO2016096778 (Roche), WO2017190669 (Shanghai De Novo Pharmatech), US09884866 (University of Minnesota), WO2017219931 (Sichuan KelunBiotech Biopharmaceutical), WO2018002319 (Janssen Sciences), WO2017216054 (Roche), WO2017202703 (Roche), WO2017184735 (IFM Therapeutics), WO2017184746 (IFM Therapeutics), WO2015088045 (Takeda Pharmaceutical), WO2017038909 (Takeda Pharmaceutical), WO2015095780 (University of Kansas), WO2015023958 (University of Kansas).

[0404] In some embodiments, the compound as described herein or a pharmaceutically acceptable salt thereof is co-administered with a TLR7, TLR8, TLR9 agonist or a combination thereof. Interferon α-receptor ligand

[0405] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one interferon α receptor ligand. Examples of interferon α receptor ligands include interferon α-2b (INTRON A®), pegylated interferon α-2a (PEGASYS®), pegylated interferon α-1b, interferon α-1b (HAPGEN®), Veldona, Infradure, Roferon-A, YPEG-interferon α-2a (YPEG-rhIFNα-2a), P-1101, Algeron, Alfarona, Ingaron (interferon γ), rSIFN-co (recombinant high-efficiency complex interferon), Ypeg interferon α-2b (YPEG-rhIFNα-2b), MOR-22, pegylated interferon α-2b (PEG-INTRON®), Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon α-n1 (HUMOFERON®), and interferon β-1a (AVONEX). ®), Shaferon, Interferon α-2b (Axxo), Alfaferone, Interferon α-2b (BioGeneric Pharma), Interferon-α 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, Interferon α-2b (IFN, Laboratorios Bioprofarma), Interferon α 2b, Kalferon, Pegnano, Feronsure, PegiHep, Interferon α 2b (Zydus-Cadila), Interferon α 2a, Optipeg A, Realfa 2B, Reliferon, Interferon α-2b (Amega), Interferon α-2b (Virchow), Ropeg Interferon α-2b, rHSA-IFNα-2a (Recombinant Human Serum Albumin Interferon α 2a Fusion Protein), rHSA-IFNα 2b. Recombinant human interferon α-(1b, 2a,2b) Pegylated interferon α-2b (Amega), pegylated interferon α-2a, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon α-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFNα-2b, SFR-9216, and Interapo (Interapa). Another example of an interferon α receptor ligand includes (but is not limited to) PEG-IFN-α. Hyaluronidase inhibitor

[0406] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one hyaluronidase inhibitor. Examples of hyaluronidase inhibitors include atomail. Hepatitis B surface antigen (HBsAg) inhibitors

[0407] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one hepatitis B surface antigen inhibitor. Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031, and REP-006, as well as REP-9AC′. Another example of an HBsAg inhibitor includes GP-605.

[0408] Examples of HBsAg secretion inhibitors include BM601. Other examples of HBsAg secretion inhibitors include (but are not limited to) GST-HG-131, AB-452, ALG-010093, and combinations thereof. Cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors

[0409] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitor. Examples of cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilimumab, beracipex, PSI-001, PRS-010, Probody mAbs, trimemumab, and JHL-1155. Cyclophilic inhibitors

[0410] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one cyclophilin inhibitor. Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and compounds described in US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), and US20130344029 (Gilead Sciences). HBV virus enters inhibitor

[0411] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HBV entry inhibitor. Examples of HBV entry inhibitors include Myrcludex B. Hepatitis B macrophage inhibitors

[0412] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one hepatitis B mantle protein inhibitor. Examples of hepatitis B mantle protein inhibitors include (but are not limited to) GP-605, GST-HG-121, ALG-010093, and ALG-01013. Antisense oligonucleotides targeting viral mRNA

[0413] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one antisense oligonucleotide targeting viral mRNA. Examples of antisense oligonucleotides targeting viral mRNA include ISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, and RG-6004. Other examples of antisense oligonucleotides targeting viral mRNA include (but are not limited to) IONIS-HBV-LRx, BNC-1701, and combinations thereof. Short interfering RNA (siRNA) and ddRNAi

[0414] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one siRNA and / or ddRNAi agent.

[0415] Examples of siRNAs include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, and ARB-1467. Other examples of siRNAs include (but are not limited to) AB-729, DCR-HBVS, RG-6084 (PD-L1), RG-6217, ALN-HBV-02, JNJ-3989 (ARO-HBV), STSG-0002, ALG-010133, ALG-ASO, LUNAR-HBV, DCR-HBVS (DCR-S219), and combinations thereof.

[0416] Examples of DNA-guided RNA interference (ddRNAi) agents include BB-HB-331. Intranuclease regulators

[0417] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one endonuclease regulator. Examples of endonuclease regulators include PGN-514.

[0418] In some embodiments, ribonucleotide reductase inhibitors are combinations of compounds described herein or pharmaceutically acceptable salts thereof with at least one ribonucleotide reductase inhibitor. Examples of ribonucleotide reductase inhibitors include remedullary ribonucleotide reductase inhibitors. Non-nucleoside reverse transcriptase inhibitors

[0419] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one non-nucleoside reverse transcriptase inhibitor. Examples of non-nucleoside reverse transcriptase inhibitors (NNRTIs) include, but are not limited to, the compounds disclosed in WO2018118826 (Merck), WO2018080903 (Merck), WO2018119013 (Merck), WO2017100108 (Idenix), WO2017027434 (Merck), WO2017007701 (Merck), and WO2008005555 (Gilead). HBV replication inhibitors

[0420] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one HBV replication inhibitor. Examples of hepatitis B virus replication inhibitors include (but are not limited to) GP-31502, isothifludin, IQP-HBV, RM-5038, and singatil. HIV-1 reverse transcriptase inhibitors

[0421] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HIV-1 reverse transcriptase inhibitor. Examples of HIV-1 reverse transcriptase inhibitors include (but are not limited to) 2,5,6-substituted pyrimidinone derivatives (HBV). Inhibitors of non-standard RNA polymerases PAPD5 and PAPD7

[0422] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one non-canonical RNA polymerase PAPD5 and / or PAPD7 inhibitor. Examples of non-canonical RNA polymerase PAPD5 and PAPD7 inhibitors include (but are not limited to) inhibitors targeting PAPD5 and PAPD7. [Lock] Antisense oligonucleotides (HBV infection). HBV E antigen inhibitors

[0423] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HBV E antigen inhibitor. Examples of HBV E antigen inhibitors include baicalein. Covalently closed circular DNA (cccDNA) inhibitors

[0424] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one cccDNA inhibitor. Examples of cccDNA inhibitors include BSBI-25 and CHR-101. Another example of a cccDNA inhibitor includes (but is not limited to) ccc-R08. Farnesol X receptor agonists

[0425] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one farnesoid X receptor (FXR) agonist. Examples of farnesoid X receptor agonists are, for example, EYP-001, GS-9674, EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297, and GS-8670. Another example of a farnesoid X receptor agonist is cilofexor. Caspase-9 stimulator

[0426] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one caspase-9 stimulator. Examples of caspase-9 stimulators include (but are not limited to) ENOB-HB-01. CD3 modulators

[0427] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one CD3 modulator. Examples of CD3 modulators include (but are not limited to) IMC-I109V. Ffar2 and Ffar3 agonists

[0428] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one Ffar2 and / or Ffar3 agonist. Examples of Ffar2 and Ffar3 agonists include (but are not limited to) SFA-001. HBV antibody

[0429] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one HBV antibody. Examples of HBV antibodies targeting the surface antigen of hepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and whole-human monoclonal antibody therapy (Hepatitis B virus infection, Humabs BioMed). Other examples of HBV antibodies targeting the surface antigen of hepatitis B virus include lenvervimab, VIR-3434, and combinations thereof.

[0430] Examples of HBV antibodies (including monoclonal and polyclonal antibodies) include Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

[0431] Human monoclonal antibodies include HBC-34.

[0432] Antibodies against HBV viral peptide / major histocompatibility complex (MHC) class I (pMHC) complexes are described, for example, in Sastry et al., J Virol. 2011 Mar;85(5):1935-42 and WO2011062562. CCR2 chemokine antagonists

[0433] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one CCR2 chemokine antagonist. Examples of CCR2 chemokine antagonists include propargite germanium. thymosin agonists

[0434] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one thymosin agonist. Examples of thymosin agonists include thymosin alpha 1 and recombinant thymosin alpha 1 (GeneScience). Cytokines

[0435] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with at least one interleukin. Examples of interleukins include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and simmoleukin. interleukin agonists

[0436] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with interleukin agonists (including, but not limited to, IL-2, IL-7, IL-15, IL-10, and IL-12 agonists); examples of IL-2 agonists include, for example, prazolam (aldeleukin, IL-2), PEGylated IL-2 (e.g., NKTR-214), modified IL-2 variants (e.g., THOR-707), bepecide-aldeleukin, AIC-284, ALKS-4230, CUI-101, and Neo-2 / 15; examples of IL-15 agonists include, for example... Examples of IL-7 include ALT-803, NKTR-255 and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 soinholm (polyethylene glycolated IL-15), P-22339 and IL-15-PD-1 fusion protein N-809; examples of IL-7 include CYT-107. Nucleoprotein regulators

[0437] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one nucleoprotein modulator. The nucleoprotein modulator may be an HBV core or capsid protein inhibitor. Examples of nucleoprotein modulators include GS-4882, AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, and BAY 41-4109. [、] Morphothiadine mesilate, ARB-168786, ARB-880, JNJ-379, RG-7907, HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158 and DVR-23. Other examples of nucleoprotein modulators include (but are not limited to) AB-836, AT-130, ALG-001075, ALG-001024, ALG-000184, EDP-514, ARB-1820, GST-HG-141, JNJ-632, GST-HG-141, KL-060332, ABI-H3733, AK-0605, HRS-5091, VNRX-9945, CB-HBV-001, AK-0605, SOC-10, SOC-11, and combinations thereof.

[0438] Examples of capsid inhibitors include compounds described in the following cases: US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015 / 059212 (Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652 (Novira), US20150259324, (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche), WO2017198744 (Roche), US 20170334882 (Novira), US 20170334898 (Roche), WO2017202798 (Roche), WO2017214395 (Enanta), WO2018001944 (Roche), WO2018001952 (Roche), WO2018005881 (Novira), WO2018005883 (Novira), WO2018011100 (Roche), WO2018011160 (Roche), WO2018011162 (Roche), WO2018011163 (Roche), WO2018036941 (Roche), WO2018043747 (Kyoto Univ), US20180065929 (Janssen)、WO2016168619(Indiana University), WO2016195982 (The Penn State Foundation), WO2017001655 (Janssen), WO2017048950 (Assembly Biosciences), WO2017048954 (Assembly Biosciences), WO2017048962 (Assembly Biosciences), US20170121328 (Novira), US20170121329 (Novira). Other examples of capsid inhibitors include (but are not limited to) those disclosed in US2018161307 (Gilead Sciences).

[0439] Examples of transcript inhibitors include those described in WO2017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche), WO2017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655 (Roche), WO2016161268 (Enanta), WO2017001853 (Redex Pharma), WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis), WO2018019297 (Ginkgo Pharma), WO2018022282 (Newave Pharma), US20180030053 (Novartis), and WO2018045911. Compounds from (Zhejiang Pharma). STING agonists, RIG-I and NOD2 modulators

[0440] In some embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined with interferon gene stimulating factor (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of: ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, STINGVAX, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthonone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP. In some embodiments, the agents described herein are combined with RIG-1 modulators (e.g., RGT-100) or NOD2 modulators (e.g., SB-9200 and IR-103).

[0441] Examples of STING agonists include (but are not limited to) those disclosed in WO 2018065360 (Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466 (Aduro Biotech), WO 2017186711 (InvivoGen), WO 2017161349 (Immune Sensor), WO 2017106740 (Aduro Biotech), US 20170158724 (Glaxo Smithkline), WO 2017075477 (Aduro Biotech), US 20170044206 (Merck), WO 2014179760 (University of California), WO2018098203 (Janssen), WO2018118665 (Merck), and WO2018118664. The compounds in (Merck), WO2018100558 (Takeda), WO2018067423 (Merck) and WO2018060323 (Boehringer). Retinol can induce gene 1 stimulators

[0442] In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are combined with at least one retinoic acid-inducible gene 1 stimulator. Examples of retinoic acid-inducible gene 1 stimulators include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, ORI-7170, and RGT-100. Another example of a retinoic acid-inducible gene 1 stimu...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: , , , , , , , , , or, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or its pharmaceutically acceptable salt thereof is: , or its pharmaceutically acceptable salt thereof.

3. The compound or its pharmaceutically acceptable salt as claimed in item 1 is: .

4. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1 to 3 of the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

5. The pharmaceutical composition of claim 4, further comprising at least one other therapeutic agent.

6. The pharmaceutical composition of claim 5, wherein the at least one other therapeutic agent comprises an anti-HIV agent.

7. The pharmaceutical composition of claim 5, wherein the at least one other therapeutic agent comprises an HIV integrase inhibitor, an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversal agent, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, other drugs for the treatment of HIV, or combinations thereof.

8. The pharmaceutical composition of claim 5, wherein the at least one other therapeutic agent comprises abacavir, tenofovir alafenamide, or tenofovir disoproxil fumarate. disoproxil), emtricitabine, bictegravir, dolutegravir, cabotegravir, N-((S)-l-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopent[l,2-c]pyrazol-l-yl)acetamide, pharmaceutically acceptable salts thereof, or combinations thereof.

9. The pharmaceutical composition of any one of claims 4 to 8, wherein the pharmaceutical composition is for oral or non-enteral administration.

10. The pharmaceutical composition of claim 5, wherein the at least one other therapeutic agent comprises an anti-HBV agent.

11. The pharmaceutical composition of claim 5, wherein the at least one other therapeutic agent comprises an HBV combination drug, an HBV vaccine, an HBV DNA polymerase inhibitor, an immunomodulator, a TLR receptor modulator, an interferon alpha receptor ligand, a hyaluronidase inhibitor, a hepatitis B surface antigen (HBsAg) inhibitor, a cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitor, a cyclophilin inhibitor, an HBV virus entry inhibitor, an antisense oligonucleotide targeting viral mRNA, a short interfering RNA (siRNA) and ddRNAi intranuclease modulator, a ribonucleotide reductase inhibitor, an HBV E antigen inhibitor, or a covalently closed circular DNA. (cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein regulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin α-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, and other drugs and combinations thereof used to treat HBV.

12. The pharmaceutical composition of claim 5, wherein the at least one other therapeutic agent comprises adefovir, entecavir, telbivudine, lamivudine, or a combination thereof.

13. Use of a compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 4 to 12, for the manufacture of an agent for treating a human with HIV infection.

14. As claimed in claim 13, wherein the drug is administered orally, intravenously, subcutaneously, or intramuscularly.